BR112015006726B1 - COMPOUND, PHARMACEUTICAL COMPOSITION, AND, USE OF A COMPOUND OR A PHARMACEUTICAL COMPOSITION - Google Patents

Abstract

COMPOUND, PHARMACEUTICAL COMPOSITION, AND, USE OF A COMPOUND OR A PHARMACEUTICAL COMPOSITION. The present invention provides heteroaromatic derivatives and acceptable pharmaceutical salts and formulations thereof useful in modulating protein kinase activity, especially phosphatidylinositol 3-kinases (PI3 kinases) and mTOR and in modulating inter- and/or intracellular signaling activities such as proliferation , differentiation, apoptosis, migration and invasion. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in treating hyperproliferative disorders in mammals, especially humans.

Description

CROSS REFERENCE TO RELATED ORDER

[001] This application claims the benefit of U.S. Provisional Application Serial Number 61/726,139, filed November 14, 2012, which is hereby incorporated by reference in its entirety.

FIELD OF INVENTION

[002] The invention disclosed herein refers to the field of protein kinases and inhibitors thereof. In particular, the invention concerns modulators of the signaling pathways of phosphatidylinositol 3-kinases (PI3 kinases or PI3Ks), and methods of using them.

FUNDAMENTALS OF THE INVENTION

Phosphoinositide 3-kinases (PI3 kinases or PI3Ks), a family of lipid kinases, have been discovered to have key regulatory roles in many cellular processes including cell survival, proliferation and differentiation. As major downstream effectors of receptor tyrosine kinases (RTKs) and G protein-linked receptors (GPCRs), PI3Ks transduce signals from various growth factors and cytokines into intracellular messages by generating phospholipids, which activate the protein serine-threonine kinase AKT (also known as protein kinase B (PKB)) and other downstream effector pathways. Tumor suppressor or PTEN (phosphatase and tensin homologue) is the most important negative regulator of the PI3K signaling pathway *"Small molecule inhibitors of the RK5M0 signaling network" Future Med. Chem., 2011, 3(5) , 549-565).

The phosphoinositide 3-kinase (PI3K) pathway is an important signal transduction pathway commonly activated in cancer. Activated PI3K pathways lead to phosphorylation of phosphatidylinositol-4,5-bisphosphate (PIP2) to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3). PIP3 can be dephosphorylated by phosphatase and tensin homolog (PTEN), which terminates PI3K signaling. PIP3 accumulation activates a signaling cascade starting with the phosphorylation (activation) of the protein serine-threonine kinase AKT to threonine 308 by phosphoinositide-dependent kinase 1 (PDK1). Phosphorylated AKT activates the mammalian target of rapamycin (mTOR), which leads to phosphorylation of its downstream target.

[005] There are three classes of PI3K, with different structures and characteristics; class I can be further subdivided into class Ia and class Ib. Class II PI3Ks are large proteins (170 to 210 kDa) that have one of the catalytic domains that mediate calcium/lipid binding in C isoforms of classical protein kinase C . Class III PI3Ks are typified by the yeast protein encoded by the VPS34 gene and phosphorylates only PtdIns to produce PtdIns(3)P; they are considered to regulate bladder transport (Targeting PI3K signaling in cancer: opportunities, challenges and limitationsSo” Nature Review Cancer, 2009, 9, 550).

The class Ia PI3Ks *RK5Mg, RK5Mβ, RK5My and RK5Mh+ comprise heterodimers between a catalytic subunit of p110 *r332g. r332β, r332y and r332h respectively), and one of the p85 regulatory adapter subunits (ie, r:7g, r:7β, r77h, r77g and r72g+0 The catalytic p110 subunit uses ATP to phosphorylate Ptdlns, PtdIns4P and PtdIns 5) P2. The importance of Class Ia PI3Ks in cancer was confirmed by the discovery that the PI3K catalytic subunit g isoform gene (PIK3CA), which encodes p110, is often mutated or amplified in various human tumors such as ovarian cancer (Campbell et al, Cancer Res 2004, 64, 7678-7681 ; Levine et al., Clin Cancer Res 2005, 11, 2875-2878; Wang et al., Hum Mutat 2005, 25, 322; Lee et al., Gynecol Oncol 2005 , 97, 26-34), cervical cancer, breast cancer (Bachman, et al. Cancer Biol Ther 2004, 3, 772775; Levine, et al., supra; Li et al., Breast Cancer Res Treat 2006, 96, 91 -95; Saal et al., Cancer Res 2005, 65, 2554-2559; Samuels and Velculescu, Cell Cycle 2004, 3, 1221-1224), colorectal cancer ( Samuels, et al. Science 2004, 304, 554; Velho et al. al.Eur J Cancer 200 5, 41, 1649-1654), endometrial cancer (Oda et al. Cancer Res. 2005, 65, 10669-10673), gastric carcinomas (Byun et al., MJ Cancer 2003, 104, 318-327; Li et al., supra; Velho et al., supra; Lee et al., Oncogene 2005, 24, 1477-1480), hepatocellular carcinoma (Lee et al., id), small and non-small cell lung cancer (Tang et al., Lung Cancer 2006, Jl, 181-191; Massion et al., Am J Respir Crit Care Meaf 2004, 170, 1088-1094), thyroid carcinoma (Wu et al, J Clin Endocrinol Metab 2005, 90, 4688-4693), acute myelogenous leukemia (AML) (Sujobert et al., Blood 1997, 106, 1063-1066), chronic myelogenous leukemia (CML) (Hickey and Cotter J Biol Chem 2006, 281, 2441-2450), and glioblastomas (Hartmann et al. Acta Neuropathol (Berl) 2005, 109, 639-642; Samuels et al., supra).

[007] mTOR is a highly conserved serine-threonine kinase with lipid kinase activity and participates as an effector in the PI3K/AKT pathway. mTOR exists in two distinct complexes, mTORC1 and mTORC2, and plays an important role in cell proliferation by monitoring nutrient availability and cellular energy levels. The downstream targets of mTORC1 are ribosomal protein S6 kinase 1 and eukaryotic translation initiation factor 4E binding protein 1, both of which are crucial for the regulation of protein synthesis. *“Rtgugnt and future of PI3K inhibition pathway in cancer: perspectives and limitations” Current Med. Chem. 2011, 18, 2647-2685).

[008] Knowledge about the consequences of deregulated mTOR signaling for tumorigenesis mainly originates from studies of pharmacologically discontinuation of mTOR by repamycin and its analogues such as temsirolimus (CCI-779) and everolimus (RAD001). Rapamycin has been found to inhibit mTOR and thereby induce G1 paralysis and apoptosis. The mechanism of growth inhibition by rapamycin was found to be related to the formation of complexes of rapamycin with FK binding protein 12 (FKBP-12). These complexes then bind with high affinity to mTOR, preventing activation and resulting in inhibition of protein translation and cell growth. The cellular effects of mTOR inhibition are even more pronounced in cells that have concomitant PTEN inactivation. Rapamycin's antitumor activity was subsequently identified, and several rapamycin analogues such as temsirolimus and everolimus were approved by the US Food and Drug Adminstration for the treatment of certain types of cancer.

[009] In view of the important role of PI3Ks and mTOR in biological processes and disease states, inhibitors of these kinases are desirable. “Rtqitess in the preclinical discovery and clinical development of class I and dual class I/IV phosphoinositide 3-kinase (PI3K) inhibitors0” Current Med Chem 2011, 18, 2686-2714).

SUMMARY OF THE INVENTION

[0010] The following only summarizes certain aspects of the invention and is not intended to be limiting in nature. These aspects and other aspects and embodiments are described more fully below. All references cited in this specification are hereby incorporated by reference in their entirety. In the event of a discrepancy between the express disclosure of this descriptive report and the references incorporated by reference, the express disclosure of this descriptive report shall control.

Provided herein are compounds that inhibit, regulate, and/or modulate PI3K and/or mTOR, and are useful in the treatment of hyperproliferative diseases, such as cancer, in humans. Also provided herein are methods of making the compound, methods of using such compounds in the treatment of hyperproliferative diseases in humans, and pharmaceutical compositions containing such compounds.

ou um estereoisômero, um isômero geométrico, um tautômero, um N-óxido, um solvato, um metabólito, um sal farmacêutico ou um pró-medicamento dos mesmos, em que cada um de Y, Z, R1, W1, W2 e W3 é como aqui definido.[0012] The first aspect of the invention provides a compound of Formula (I):

or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutical salt, or a prodrug thereof, wherein each of Y, Z, R1, W1, W2 and W3 is as defined herein.

[0013] In certain embodiments, each of W1, W2 and W3 is independently N or CRc;

;[0014] Z is D, CN, N3 or

;

[0015] X is H, D, alkyl (C1-C6), cycloalkyl (C3-C6), heterocyclyl (C3-C6), -alkylene(C1-C4)-cycloalkyl(C3-C6), -alkylene(C1- C4)- heterocyclyl (C3-C6), aryl (C6-C10), or 5- to 10-membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, wherein each is (C1-alkyl) C6), cycloalkyl (C3-C6), heterocyclyl (C3-C6), -alkylene (C1-C4)-cycloalkyl (C3-C6), -alkylene (C1-C4)-heterocyclyl (C3-C6), aryl (C6 -C10) and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, CN, N3, ORa, SRa, NRaRb, -C(=O)NRaRb , alkyl (C1-C6), haloalkyl (C1-C6), alkenyl (C2-C6), alkynyl (C2-C6), -alkylene (C1-C4)-CN, -alkylene (C1-C4)-ORa, - (C1-C4)alkylene-NRaRb, (C6-C10) aryl, and 5- to 10-membered heteroaryl;

[0016] Y is alkyl (C1-C6), cycloalkyl (C3-C6), heterocyclyl (C3-C6), -alkylene (C1-C4)-cycloalkyl (C3-C6), -alkylene (C1-C4)-heterocyclyl (C3C6), alkenyl (C2-C6), alkynyl (C2-C6), aryl (C6-C10) or 5- to 10-membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, in that each of alkyl (C1-C6), cycloalkyl (C3-C6), heterocyclyl (C3-C6), -alkylene (C1-C4)-cycloalkyl (C3-C6), - alkylene (C1-C4)-heterocyclyl ( C3-C6), alkenyl (C2-C6), alkynyl (C2-C6), aryl (C6-C10) and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F , Cl, Br, CN, N3, ORa, SRa, NRaRb, -C(=O)NRaRb, alkyl (C1-C6), haloalkyl (C1C6), alkenyl (C2-C6), alkynyl (C2-C6), - (C 1 -C 4 )alkylene-CN, -(C 1 -C 4 )alkylene-ORa, -(C 1 -C 4 )alkylene-NRaRb, (C 6 -C 10 ) aryl, and 5- to 10-membered heteroaryl;

[0017] R1 is H, D, Cl, ORa, NRaRb, aliphatic (C1-C6) or cycloalkyl (C3-C6), wherein each of the aliphatic (C1-C6) and cycloalkyl (C3-C6) is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, CN, N3, ORa, SRa and NRaRb, provided that when each of W1, W2 and W3 is CH, R1 is not H or NH2;

[0018] Each of Ra and Rb is independently H, alkyl (C1-C6), cycloalkyl (C3-C6), heterocyclyl (C3-C6), aryl (C6-C10), 5- to 10-membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, -(C 1 -C 4 )alkylene- (C 6 -C 10 )aryl or -(C 1 -C 4 )alkylene-(5- to 10-membered heteroaryl); or when Ra and Rb are attached to the same nitrogen atom, Ra and Rb, together with the nitrogen atom to which they are attached, optionally form a substituted or unsubstituted 3- to 8-membered heterocyclic ring, wherein each of the alkyl (C1-C6), cycloalkyl (C3-C6), heterocyclyl (C3-C6), aryl (C6-C10), and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, CN, N3, OH, NH2, (C1-C6)alkoxy, and (C1-C6)alkylamino; and

[0019] each Rc is independently H, D, F, Cl, Br, I, N3, CN, OH, NH2, alkyl (C1-C6), alkoxy (C1-C6), alkyl (C1-C6) amino, cycloalkyl (C3C6), heterocyclyl (C3-C6), aryl (C6-C10), or 5- to 10-membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, where each of (C1) alkyl -C6), alkoxy (C1-C6), alkyl (C1-C6) amino, cycloalkyl (C3-C6), heterocyclyl (C3-C6), aryl (C6-C10) and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, CN, N3, OH, NH2, alkyl (C1C6), cycloalkyl (C3-C6), haloalkyl (C1-C6), alkoxy (C1-C6) and (C1-C6) alkylamino.

[0020] In another embodiment, each of W1 and W2 is independently N or CRc, W3 is CRc.

[0021] In another embodiment, Z is CN, N3 or ’^x.

[0022] In another embodiment, X is H, D, alkyl (C1-C6), cycloalkyl (C3-C6), heterocyclyl (C3-C6), -alkylene (C1-C4)-cycloalkyl (C3C6) or -(C1-C4)alkylene-(C3-C6)heterocyclyl, wherein each of (C1-C6)alkyl, (C3-C6) cycloalkyl, (C3-C6) heterocyclyl, (C1-C4)alkylene-cycloalkyl (C3-C6) and -(C1-C4)alkylene-heterocyclyl (C3-C6) is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, CN, N3, ORa, SRa , NRaRb, -C(=O)NRaRb, alkyl (C1-C6), haloalkyl (C1-C6), alkenyl (C2-C6) and alkynyl (C2-C6).

[0023] In another embodiment, Y is alkyl (C1-C6), cycloalkyl (C3-C6), alkenyl (C2-C6), alkynyl (C2-C6), aryl (C6-C10), or heteroaryl of 5 to 10 members comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, wherein each of alkyl (C1C6), cycloalkyl (C3-C6), alkenyl (C2-C6), alkynyl (C2-C6 ), aryl (C6-C10) and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, CN, N3, ORa, SRa, NRaRb, -C (=O)NRaRb, alkyl (C1-C6), haloalkyl (C1-C6), alkynyl (C2C6), aryl (C6-C10) and 5- to 10-membered heteroaryl.

[0024] In another embodiment, R1 is H, D, Cl, CH3, CH2CH3, CF3, CH2CF3, OCH3, OCH2CH3, NH2, NHCH3 or N(CH3)2, provided that when each of W1, W2 and W3 is CH, R1 is not H or NH2.

[0025] In another embodiment, each Rc is independently H, D, F, Cl, N3, CN, NH2, alkyl (C1-C3), alkoxy (C1-C3), alkyl (C1-C3) amino, cycloalkyl (C3-C6) or heterocyclyl (C3-C6), wherein each of alkyl (C1-C3), alkoxy (C1-C3), alkyl (C1-C3) amino, cycloalkyl (C3-C6) and heterocyclyl ( C3-C6) is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, CN, N3, OH, NH2, alkyl (C1-C3), cycloalkyl (C3-C6) and haloalkyl (C1-C3 ).

[0026] In another aspect, provided herein are pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable stereoisomer, geometric isomer, tautomer, solvate, metabolite, salt or prodrug thereof, and a carrier, excipient, diluent, optional pharmaceutically acceptable adjuvant, carrier or a combination thereof. In certain embodiments, the compound is a PI3K modulator.

[0027] In some embodiments, the pharmaceutical composition disclosed herein further comprises an additional therapeutic agent. In other embodiments, the therapeutic agent is a chemotherapeutic agent, an anti-proliferative agent, an agent to treat atherosclerosis, an agent to treat pulmonary fibrosis, or a combination thereof.

In certain embodiments, the additional therapeutic agent is chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozocine, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracila, citea mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunorubicin, mitoxantrone, bleomycin, gooxitambemcin, fludomycin, bleomycin, mitoxitamycin, fludomycin, fludomycin dexamethasone, methylprednisolone, thalidomide, interferon alpha, leucovorin, sirolimus, tensirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brivanib, cabozantinib, cedibtinib dab, dabtininib, cretinib, dabtininib, dab erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotin ib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, sarertinib, rego sorafenib, sunitinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, alemtuzumab, bevacizumab, brentuximab, brentuximab, tumabximab, tumaboxime, cathuzuma, , rituximab, tositumomab, trastuzumab, or a combination thereof.

[0029] In another aspect, provided herein are methods for preventing, controlling, treating or lessening the severity of a proliferative disorder in a patient infected with the proliferative disorder, which comprises administering a pharmaceutically effective amount of the compound disclosed herein, or the composition pharmaceutical here disclosed to the patient.

[0030] In another aspect, provided herein is the use of the compound disclosed herein, or the pharmaceutical composition disclosed herein, in the manufacture of a medicament for preventing, controlling, treating or lessening the severity of a proliferative disorder in a patient.

[0031] In some embodiments, the proliferative disorder is metastatic cancer. In other embodiments, the proliferative disorder is colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, skin cancer, thyroid cancer, head and neck cancer, prostate cancer , pancreatic cancer, CNS cancer, glioblastoma or a myeloproliferative disorder. In other embodiments, the proliferative disorder is atherosclerosis or pulmonary fibrosis.

[0032] In another aspect, provided herein is a method of inhibiting or modulating the activity of PI3K and/or mTOR in a biological sample comprising contacting a biological sample with the compound disclosed herein, or the pharmaceutical composition disclosed herein.

In some embodiments, provided herein is a method of inhibiting or modulating PI3K or mTOR, the method comprising contacting the kinase with the compound according to the present invention, or with the composition according to the present invention. In some embodiments, the invention provides a method of inhibiting or modulating PI3K or mTOR signaling, the method comprising contacting the receptor with the compound according to the present invention, or with the composition according to the present invention. In some embodiments, the inhibition or modulation of PI3K or mTOR activity can be in a cell or a multicellular organism. If in a multicellular organism, the method according to this aspect of the invention comprises administering to the organism the compound according to the present invention, or the composition according to the present invention. In some embodiments, the organism is a mammal. In other embodiments it is a human. In yet another embodiment, the method further comprises contacting the kinase with an additional therapeutic agent.

[0034] In another aspect, provided herein is a method of inhibiting the proliferative activity of a cell, the method comprising contacting the cell with an effective proliferative inhibitory amount of a compound according to the present invention or a composition thereof. In some embodiments, the method further comprises contacting the cell with an additional therapeutic agent.

[0035] In another aspect, provided herein is a method of treating a cell proliferative disease in a patient, the method comprising administering to the patient in need of such treatment a therapeutically effective amount of the compound according to the present invention or the composition the same. In some embodiments, the method further comprises administering an additional therapeutic agent.

[0036] In some embodiments, provided herein is a method of inhibiting tumor growth in a patient, the method comprising administering to the patient in need thereof an effective therapeutic amount of the compound according to the present invention or the composition thereof . In some embodiments, the method further comprises administering an additional therapeutic agent.

[0037] In another aspect, provided herein includes methods of preparing, methods of separating, and methods of purifying compounds of Formula (I).

[0038] The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting in nature. These aspects and other aspects and embodiments are described more fully below.

DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS AND GENERAL TERMINOLOGY

[0039] Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the appended structures and formulas. The invention is intended to encompass all alternatives, modifications, and equivalents that may be included within the scope of the present invention as defined by the claims. A person of skill in the art will recognize many methods and materials similar or equivalent to those described herein that can be used in the practice of the present invention. The present invention is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differ from or contradict this application, including but not limited to the terms, term usage, described techniques, or the like as defined, this application governs.

[0040] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by a person of skill in the art to which this invention belongs. All patents and publications referenced herein are incorporated by reference.

[0041] As used herein, the following definitions shall apply unless otherwise indicated. For the purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, and the Handbook of Chemistry and Physics, 75th Ed. 1994. Additionally, general principles of organic chemistry are described in "Qtiâpke EjgoiuVty ” Thomas Sorrell, University Science Books, Sausalito: 1999, and “Marcus Advanced Organic EjgokuVty” by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are hereby incorporated by reference .

[0042] As used in the specification and claims, the term "a," "an," "the" and similar terms used in the context of the present invention shall be interpreted to encompass both the singular and the plural unless otherwise noted. here indicated or clearly contradicted by the context.

[0043] As used herein, the term "individual" refers to an animal. Typically the animal is a mammal. An individual also refers to, for example, primates (eg, humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the individual is a primate. In other embodiments, the individual is a human being.

[0044] As used herein, "patient" refers to a human (including adults and children) or other animal. In one embodiment, "patient" refers to a human being.

[0045] The present invention also includes isotopically labeled compounds, which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or number of mass usually found in nature. Some non-limiting examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, 2 3 13 14 15 17 18 31 32 36 18 37 such as H, H, C , C, N, O, O, P, P, S, F, and Cl.

[0046] The compounds disclosed herein which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically labeled compounds disclosed herein, for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotypes are particularly preferred for their ease of preparation and detection. In addition, substitution with heavier isotopes such as deuterium, i.e., 2H, can provide certain therapeutic advantages that result from greater metabolic stability, for example increased requirements on in vivo half-life or reduced dosage and, consequently, may be preferred in some circumstances.

Stereochemical definitions and conventions used generally herein follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane polarized light in the plane. In describing an optically active compound, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecule around its chiral center(s). The prefixes d and l or (+) and (-) are used to designate the sign of rotation of plane polarized light by the compound, with (-) or l meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.

[0048] Depending on the choice of starting materials and procedures, the compounds may be present in the form of one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as isomer mixtures, such as racemates and mixtures of diastereoisomer, depending on the number of asymmetric carbon atoms. Optically active (R) and (S) isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be of the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration.

The compounds disclosed herein may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds disclosed herein, including but not limited to, diastereomers, enantiomers, atropisomers, and geometric (or conformational) isomers as well as mixtures thereof such as racemic mixtures, form part of the present invention.

Unless otherwise stated, structures depicted herein are also intended to include all isomeric forms (e.g., enantiomeric, diastereomeric, atropisomeric, and geometric (or conformational)) of the structure; for example, the R and S configurations for each asymmetric center, double bond isomers (Z) and (E), and conformational isomers (Z) and (E).

[0051] The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible through a low energy barrier. Where tautomerization is possible (eg in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions via the migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by the reorganization of some of the bonding electrons. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.

Unless otherwise stated, all tautomeric forms of the compounds disclosed herein are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms.

[0053] Any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present invention may be present in the racemic or enantiomerically enriched, e.g. S). In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) or (S) configuration. Substituents on atoms with unsaturated double bonds, if possible, may be present in cis (Z) or trans (E) form.

Accordingly, as used herein a compound disclosed herein may be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric isomers (cis or trans), diastereomers, optical isomers (antipods), racemates or mixtures thereof.

[0055] Any of the resulting mixtures of isomers can be separated based on the physicochemical differences of the constituents, on pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.

[0056] Any of the racemates resulting from final products or intermediates can be resolved into optical antipods by methods known to those skilled in the art, for example, by separating the diastereomeric salts thereof. Racemic products can also be resolved by chiral chromatography, eg high performance liquid chromatography (HPLC) using a chiral adsorbent. Preferred enantiomers can also be prepared by asymmetric synthesis. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wylen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0057] As described herein, the compounds disclosed herein may optionally be substituted with one or more substituents, as illustrated generally below, or as exemplified by the classes, subclasses, and particular species of the invention. It will be appreciated that the phrase “optionally substituted” is used interchangeably with the phrase “substituted or not substituted”. In general, the term "substituted" whether preceded by the term "optionally" or not, refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent. The term “optionally” or “optionally” means that the event or circumstance subsequently described may but need not occur, and that the description includes cases where the event or circumstance does occur and cases where it does not. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure can be replaced with more than one substituent selected from a specified group, the substituent may be the same or different at each position.

[0058] The term "alkyl" or "alkyl group" as used herein refers to a straight or branched chain saturated monovalent hydrocarbon radical of 1 to 20 carbon atoms. Unless otherwise specified, alkyl groups contain 1 to 20 carbon atoms. In some embodiments, alkyl groups contain 1 to 10 carbon atoms. In other embodiments, alkyl groups contain 1 to 8 carbon atoms. In yet other embodiments, the alkyl groups contain 1 to 6 carbon atoms. In other embodiments, alkyl groups contain 1 to 4 carbon atoms, and in other embodiments, alkyl groups contain 1 to 3 carbon atoms.

[0059] Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2- propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3 ), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3 )2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH (CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C (CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)-CH2CH(CH3)2), 3-methyl -3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3 )2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH) 3)C(CH3)3, 1-heptyl, 1-octyl, and the like. Alkyl radicals are optionally independently substituted with one or more substituents described herein.

[0060] The terms "alkyl" and the prefix "alqu-" as used herein are inclusive of both straight chain and branched saturated carbon chain.

[0061] The term "alkylene", as used herein, represents a saturated bivalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms. Unless otherwise specified, alkylene groups contain 1 to 6 carbon atoms. In some embodiments, alkylene groups contain 1 to 4 carbon atoms. In other embodiments, alkylene groups contain 1 to 2 carbon atoms. The alkylene group is exemplified by methylene (-CH2-), ethylene (-CH2CH2-), isopropylene (-CH(CH3)CH2-), and the like.

[0062] The term "alkenyl" refers to a straight or branched chain monovalent hydrocarbon radical of 2 to 12 carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon bond, sp2 double, in that the alkenyl radical may optionally be independently substituted with one or more substituents described herein, and includes radicals having "eku" and "Vtcpu" orientations, or alternatively, "E" and "Z" orientations. Preferably, the alkenyl group contains from 2 to 8 carbon atoms, more preferably, from 2 to 6 carbon atoms, and most preferably from 2 to 4 carbon atoms. Examples include, but are not limited to, ethylenyl or vinyl (-CH=CH2), allyl (-CH2CH=CH2), and the like.

[0063] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical of 2 to 12 carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon bond, sp triple, where the alkynyl radical may optionally be independently substituted with one or more substituents described herein. Preferably, the alkynyl group contains from 2 to 8 carbon atoms, more preferably from 2 to 6 carbon atoms, and most preferably from 2 to 4 carbon atoms. Examples include, but are not limited to, ethynyl (-EzEJ+, propynyl (propargyl, -CH2EzEJ+, -EzE-CH3, and the like).

[0064] The terms "aliphatic" or "aliphatic group" as used herein refer to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or that contains a or more units of unsaturation. Unless otherwise specified, aliphatic groups contain 1 to 20 carbon atoms. In some embodiments, aliphatic groups contain 1 to 10 carbon atoms. In other embodiments, aliphatic groups contain 1 to 8 carbon atoms. In yet other embodiments, aliphatic groups contain 1 to 6 carbon atoms. In other embodiments, aliphatic groups contain 1 to 4 carbon atoms, and in other embodiments, aliphatic groups contain 1 to 3 carbon atoms. Suitable aliphatic groups include, but are not limited to, substituted or unsubstituted linear or branched alkyl, alkenyl, or alkynyl groups. For example, aliphatic (C1-C6) groups include unbranched or branched, unsubstituted or suitably substituted alkyl (C1-C6), alkenyl (C2-C6) or (C2-C6) alkynyl groups. Aliphatic groups herein are optionally independently substituted with one or more substituents described herein.

[0065] The term "alkoxy" as used herein, refers to an alkyl group, as defined above, attached to the main carbon atom through an oxygen atom. Unless otherwise specified, alkoxy groups contain 1 to 20 carbon atoms. In some embodiments, alkoxy groups contain 1 to 10 carbon atoms. In other embodiments, alkoxy groups contain 1 to 8 carbon atoms. In still other embodiments, alkoxy groups contain 1 to 6 carbon atoms, and in other embodiments, alkoxy groups contain 1 to 3 carbon atoms.

[0066] Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2- propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-1-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH3)3 ), 1-pentoxy (n-pentoxy, -OCH2CH2CH2CH2CH3), 2-pentoxy (-OCH(CH3)CH2CH2CH3), 3-pentoxy (-OCH(CH2CH3)2), 2-methyl-2-butoxy (-OC(CH3 )2CH2CH3), 3-methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-methyl-1-butoxy (-OCH2CH2CH(CH3)2), 2-methyl-1-butoxy (-OCH2CH (CH3)CH2CH3), and the like. Alkoxy radicals are optionally independently substituted with one or more substituents described herein.

[0067] The terms "haloalkyl" and "haloalkoxy" mean alkyl, or alkoxy, as the case may be, substituted with one or more halogen atoms.

The term "alkylamino" embraces "N-alkylamino" and "N,N-dialkylamino" where the amino groups are independently substituted with one alkyl radical and two alkyl radicals, respectively. More preferred alkylamino radicals are "lower alkylamino" radicals having 1 or 2 alkyl radicals of 1 to 6 carbon atoms attached to a nitrogen atom. Even more preferred alkylamino radicals contain 1 to 3 carbon atoms. Suitable alkylamino radicals can be mono or dialkylamino such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, and the like.

[0069] The term "arylamino" indicates amino groups, which have been substituted with one or two aryl radicals, such as N-phenylamino. Arylamino radicals can be substituted further on the aryl ring portion of the radical.

The term "aminoalkyl" embraces linear or branched alkyl radicals having from one to about ten carbon atoms any one of which may be substituted with one or more amino radicals. More preferred aminoalkyl radicals are "lower aminoalkyl" radicals having one to six carbon atoms and one or more amino radicals. Some non-limiting examples of such radicals include aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl.

[0071] The terms "carbocycle", "carbocyclyl", "carbocyclic ring" and "cycloaliphatic" refer to a non-aromatic, saturated or partially unsaturated monovalent or multivalent ring having from 3 to 12 carbon atoms as a ring system monocyclic, bicyclic, or tricyclic. A bicyclic ring system includes a spiro bicyclyl or a fused bicyclyl. Suitable carbocyclyl groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Other non-limiting examples of carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1- cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, and the like.

[0072] The term "cycloalkyl" refers to a saturated monovalent or multivalent ring having from 3 to 12 carbon atoms as a monocyclic, bicyclic, or tricyclic ring system. A bicyclic ring system includes a spiro bicyclyl or a fused bicyclyl. In some embodiments, a cycloalkyl contains 3 to 10 carbon atoms. In still other embodiments, a cycloalkyl contains from 3 to 8 carbon atoms, and in other embodiments, a cycloalkyl contains from 3 to 6 carbon atoms. Cycloalkyl radicals are optionally independently substituted with one or more substituents described herein.

[0073] The term "heterocycle", "heterocyclyl" or "heterocyclic" as used interchangeably herein refers to a monocyclic, bicyclic, or tricyclic ring system in which one or more ring members are independently selected from heteroatoms and which is either fully saturated or containing one or more unsaturation units, but not aromatic, having one or more points of attachment to the rest of the molecule. A bicyclic ring system includes a spiro bicyclyl or a fused bicyclyl, and one of the rings can be a monocarbocycle or a monoheterocycle. One or more ring atoms are optionally independently substituted with one or more substituents described herein. In some embodiments, the "heterocycle", "heterocyclyl", or "heterocyclic" groups are a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O , P, and S, where the S or P is optionally substituted with one or more oxo to give the groups SO or SO2, PO or PO2). In other embodiments, they are a monocycle having 3 to 6 ring members (2 to 5 carbon atoms and 1 to 2 heteroatoms selected from N, O, P, and S, wherein the S or P is optionally substituted with one or more oxo to give the groups SO or SO2, PO or PO2) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P , and S, where the S or P is optionally substituted with one or more oxo to give the groups SO or SO2, PO or PO2).

[0074] The heterocyclyl can be a carbon radical or a heteroatom radical. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, dihydrofuranyl, homopiperazinyl, piperazinyl, thiazinyyl, thiazinyyl, o , oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, pyrazolidinyl, 1-imidazolidinyl, imidazolidinyl ,2,3,4-tetrahydro-isoquinolinyl. Some non-limiting examples of a heterocyclic group in which 2 carbon ring atoms are replaced with oxo (=O) moieties are pyrimidindionyl and 1,1-dioxo-thiomorpholinyl.

[0075] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon, including any oxidized form of nitrogen, sulfur, or phosphorus; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl).

[0076] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0077] The term "H" indicates a single hydrogen atom. This radical can be attached, for example, to an oxygen atom to form a hydroxyl radical.

[0078] The term “D” or “2H” indicates a single deuterium atom. One of this radical can be attached, for example, to a methyl group to form a mono-deuterated methyl group (-CDH2), two of deuterium atoms can be attached to a methyl group to form a di-deuterated methyl (-CD2H) , and three of deuterium atoms can be attached to a methyl group to form a tri-deuterated methyl group (-CD3).

[0079] The term "N3" indicates an azide moiety. This radical can be attached, for example, to a methyl group to form azidomethane (methyl azide, MeN3); or attached to a phenyl group to form phenyl azide (PhN3).

The term "aryl" used alone or as part of a larger portion as in "aralkyl", "aralkoxy" or "aryloxyalkyl" refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems having a total of 6 to 14 ring members, preferably 6 to 12 ring members, and more preferably 6 to 10 ring members, wherein at least one ring in the system is aromatic, wherein each ring in the system contains from 3 to 7 ring members. ring and which has one or more points of attachment to the rest of the molecule. The term "arilc" may be used interchangeably with the terms "aryla ring" or "aromatic". Some non-limiting examples of aryl rings would include phenyl, naphthyl, and anthracene. Aryl radicals are optionally independently substituted with one or more substituents described herein.

[0081] The term "heteroarylalkoxy" used alone or as part of a larger portion as in "heteroarylalkoxy" or "heteroarylalkoxy" refers to monocyclic, bicyclic, and tricyclic ring systems having a total of 5 to 14 ring members, preferably, from 5 to 12 ring members, and more preferably from 5 to 10 ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, wherein each ring in the system contains 5 to 7 ring members and has one or more points of attachment to the rest of the molecule. In some embodiments, a 5- to 10-membered heteroaryl comprises 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. The term "heteroarüc" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic". Heteroaryl radicals are optionally independently substituted with one or more substituents described herein.

[0082] Other non-limiting examples of heteroaryl rings include the following monocycles: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5- isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (eg 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (eg 5-tetrazolyl), triazolyl (eg 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (eg 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1, 2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl, and the following bicycles: benzimidazolyl, benzofuryl, benzothiophenyl, indolyl (eg 2- indolyl), purinyl, quinolinyl (eg, 2-quinolinyl, 3-quinolinyl, 4-quino linyl), and isoquinolinyl (for example, 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl).

[0083] The terms "fused bicyclic", "fused cyclic", "fused bicyclyl" and "fused cyclyl" that are used interchangeably refer to a saturated monovalent or multivalent bridged ring system, which refers to a bicyclic ring system that is not aromatic. Such a system may contain isolated or conjugated unsaturation, but no aromatic or heteroaromatic rings in its core structure (but may have aromatic substitution thereon).

The terms "spirocycline", "spirocyclic", "spiro bicyclic" or "spiro bicyclic" are used interchangeably and refer to a monovalent or multivalent ring system in which a ring originates from a particular ring carbon of another ring. For example, as depicted below in Structure a, a saturated bridged ring system (ring B and BÓ) is referred to as a "fused bicyclic", whereas ring A and ring B share an atom between the two ring systems. saturated, which is called as a "spirocycline" or "spiro bicyclinc". Each cyclic ring in a fused bicyclyl or a bicyclyl spiro can be a carbocyclyl or a heterocyclyl.

[0085] The term "unsaturated" as used herein means that a portion has one or more units of unsaturation.

[0086] The term “comprising” is intended to be unlimited, including the indicated component but not excluding other elements.

[0087] The term "pro-drug" as used herein, represents a compound that is transformed in vivo into a compound of formula (I). Such a transformation can be affected, for example, by hydrolysis in blood or enzymatic transformation from the prodrug form to the precursor form in blood or tissue. Prodrugs of the compounds disclosed herein can be, for example, esters. Esters that can be used as prodrugs in the present invention are phenyl esters, aliphatic (C1-C24) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound disclosed herein that contains an OH group can be acylated at this position in its prodrug form. Other forms of prodrug include phosphates, such as, for example, those phosphates which result from the phosphonation of an OH group on the parent compound. A full discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Pro-Drugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al, Pro-Drugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345, each of which is incorporated herein by reference.

[0088] A "metabolite" is a product produced through the metabolism in the body of a specified compound or salt thereof. Metabolites of a compound can be identified using routine techniques known in the art and their activities determined using tests such as those described herein. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound. Accordingly, the invention includes metabolites of the compounds disclosed herein, including compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0089] A "pharmaceutically acceptable salt" as used herein, refers to organic or inorganic salts of a compound disclosed herein. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences 1977, 66, 1-19, which is incorporated herein by reference. Examples of non-toxic, pharmaceutically acceptable salts include, but are not limited to, salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid , oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glycoheptonate, camphorate salts hemisulphate, heptanoate, hexanoate, iodide, 2-hydroxyethanesulphonate, lactobionate, lactate, laurate, lauryl sulphate, malate, maleate, malonate, methanesulphonate, 2-naphthalenesulphonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, persulphate , 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4 alkyl)4 salts. This invention also envisions the quaternization of any of the basic nitrogen containing groups of the compounds disclosed herein. Soluble or dispersible products in water or oil can be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C1-8 sulfonate, and aryl sulfonate.

[0090] A "solvate" refers to an association or complex of one or more solvent molecules and a compound disclosed herein. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid and ethanolamine. The term "hydrate" refers to the complex where the solvent molecule is water.

[0091] As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents , salts, preservatives, drug stabilizers, binders, excipients, disintegrating agents, lubricants, sweetening agents, flavoring agents, colorants, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except to the extent that any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is considered.

The term "a therapeutically effective amount" of a compound disclosed herein refers to an amount of the compound disclosed herein that will evoke an individual's biological or medical response, e.g., reduction or inhibition of an enzyme activity or a protein, or ameliorating symptoms, alleviating conditions, slowing or slowing disease progression, or preventing a disease, etc. In a non-limiting embodiment, the term "a therapeutically effective amount" refers to that amount of the compound disclosed herein that, when administered to a subject, is effective to (1) at least partially alleviate, inhibit, prevent and/or ameliorating a condition, or a disorder or a disease (i) mediated by PI3K or (ii) associated with PI3K activity, or (iii) characterized by (normal or abnormal) PI3K activity, or (2) reducing or inhibiting the activity of PI3K or (3) reduce or inhibit PI3K expression. In another non-limiting embodiment, the term "a therapeutically effective amount" refers to that amount of the compound disclosed herein that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reduce or inhibit PI3K activity; or at least partially reduce or inhibit PI3K expression. The meaning of the term "a therapeutically effective amount" as illustrated in the above embodiment for PI3K also applies by the same meaning to any other of the proteins/peptides/enzymes.

[0093] As used herein, the terms "treating", "treating" or "treatment" of any disease or disorder refer, in one embodiment, to ameliorating the disease or disorder (i.e., decreasing or stopping or reducing the development of the disease or at least one of its clinical symptoms). In another embodiment "treating", "treating" or "treatment" refers to the alleviation or improvement of at least one physical parameter including those that may not be discernible by the patient. In yet another embodiment, "treating", "treating" or "treatment" refers to the modulation of the disease or disorder, physically (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. in another embodiment, "treating", "treating" or "treatment" refers to preventing or delaying the onset or development or progression of the disease or disorder.

The terms "protecting group" or "PG" refer to a substituent that is commonly used to block or protect a particular functionality while reacting with other functional groups on the compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality on the compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A "carboxy protecting group" refers to a substituent on the carboxy group that blocks or protects the carboxy functionality. Common carboxy protecting groups include -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxy-methyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)-ethyl, 2- (diphenylphosphino)-ethyl, nitroethyl and the like. For a general description of protecting groups and their use, see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991 and P.J. Kocienski, Protecting Groups, Tieme, Stuttgart, 2005.

DESCRIPTION OF THE COMPOUNDS RELEASED HERE

Provided herein are aromatic compounds, salts, and pharmaceutical formulations thereof, which are potentially useful in the treatment of diseases, conditions, and disorders modulated by protein kinases, especially PI3K and mTOR. More specifically, the present invention provides a compound of Formula (I):

[0096] or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutical salt or a prodrug thereof, wherein each of Y, Z, R1, W1, W2 and W3 is as defined herein.

[0097] In certain embodiments, each of W1, W2 and W3 is independently N or CRc;

;[0098] Z È D, CN, N3 or

;

[0099] X È H, D, alkyl (C1-C6), cycloalkyl (C3-C6), heterocyclyl (C3-C6), -alkylene(C1-C4)-cycloalkyl (C3-C6), -alkylene (C1-C6) C4)- heterocyclyl (C3-C6), aryl (C6-C10), or 5- to 10-membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, where each is (C1-alkyl) C6), cycloalkyl (C3-C6), heterocyclyl (C3-C6), -alkylene (C1-C4)-cycloalkyl (C3-C6), -alkylene (C1-C4)-heterocyclyl (C3-C6), aryl (C6 -C10) and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, CN, N3, ORa, SRa, NRaRb, -C(=O)NRaRb , alkyl (C1-C6), haloalkyl (C1-C6), alkenyl (C2-C6), alkynyl (C2-C6), -alkylene (C1-C4)-CN, -alkylene (C1-C4)-ORa, - (C1-C4)alkylene-NRaRb, (C6-C10) aryl, and 5- to 10-membered heteroaryl;

[00100] Y is alkyl (C1-C6), cycloalkyl (C3-C6), heterocyclyl (C3-C6), -alkylene (C1-C4)-cycloalkyl (C3-C6), -alkylene (C1-C4)-heterocyclyl (C3C6), alkenyl (C2-C6), alkynyl (C2-C6), aryl (C6-C10) or 5- to 10-membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, in that each of alkyl (C1-C6), cycloalkyl (C3-C6), heterocyclyl (C3-C6), -alkylene (C1-C4)-cycloalkyl (C3-C6), - alkylene (C1-C4)-heterocyclyl ( C3-C6), alkenyl (C2-C6), alkynyl (C2-C6), aryl (C6-C10) and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F , Cl, Br, CN, N3, ORa, SRa, NRaRb, -C(=O)NRaRb, alkyl (C1-C6), haloalkyl (C1C6), alkenyl (C2-C6), alkynyl (C2-C6), - (C 1 -C 4 )alkylene-CN, -(C 1 -C 4 )alkylene-ORa, -(C 1 -C 4 )alkylene-NRaRb, (C 6 -C 10 ) aryl, and 5- to 10-membered heteroaryl;

[00101] R1 is H, D, Cl, ORa, NRaRb, aliphatic (C1-C6) or cycloalkyl (C3-C6), wherein each of the aliphatic (C1-C6) and cycloalkyl (C3-C6) is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, CN, N3, ORa, SRa and NRaRb, provided that when each of W1, W2 and W3 is CH, R1 is not H or NH2;

[00102] each Ra and Rb is independently H, alkyl (C1-C6), cycloalkyl (C3-C6), heterocyclyl (C3-C6), aryl (C6-C10), 5- to 10-membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, -(C 1 -C 4 )alkylene- (C 6 -C 10 )aryl or -(C 1 -C 4 )alkylene-(5- to 10-membered heteroaryl); or when Ra and Rb are attached to the same nitrogen atom, Ra and Rb, together with the nitrogen atom to which they are attached, optionally form a substituted or unsubstituted 3- to 8-membered heterocyclic ring, wherein each of the alkyl (C1-C6), cycloalkyl (C3-C6), heterocyclyl (C3-C6), aryl (C6-C10), and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, CN, N3, OH, NH2, alkoxy(C1C6), and alkyl(C1-C6)amino; and

[00103] each Rc is independently H, D, F, Cl, Br, I, N3, CN, OH, NH2, alkyl (C1-C6), alkoxy (C1-C6), alkyl (C1-C6) amino, cycloalkyl (C3C6), heterocyclyl (C3-C6), aryl (C6-C10), or 5- to 10-membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, where each of (C1) alkyl -C6), alkoxy (C1-C6), alkyl (C1-C6) amino, cycloalkyl (C3-C6), heterocyclyl (C3-C6), aryl (C6-C10) and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, CN, N3, OH, NH2, alkyl (C1C6), cycloalkyl (C3-C6), haloalkyl (C1-C6), alkoxy (C1-C6) and (C1-C6) alkylamino.

[00104] In another embodiment, each of W1 and W2 is independently N or CRc, W3 is CRc.

[00105] In another embodiment, Z is CN, N3 or x.

[00106] In another embodiment, X is H, D, alkyl (C1-C6), cycloalkyl (C3-C6), heterocyclyl (C3-C6), -alkylene (C1-C4)-cycloalkyl (C3C6) or -(C1-C4)alkylene-(C3-C6)heterocyclyl, wherein each of (C1-C6)alkyl, (C3-C6) cycloalkyl, (C3-C6) heterocyclyl, (C1-C4)alkylene-cycloalkyl (C3-C6) and -(C1-C4)alkylene-heterocyclyl (C3-C6) is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, CN, N3, ORa, SRa , NRaRb, -C(=O)NRaRb, alkyl (C1-C6), haloalkyl (C1-C6), alkenyl (C2-C6) and alkynyl (C2-C6).

[00107] In another embodiment, Y is alkyl (C1-C6), cycloalkyl (C3-C6), alkenyl (C2-C6), alkynyl (C2-C6), aryl (C6-C10) or heteroaryl of 5 to 10 members comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, wherein each of alkyl (C1C6), cycloalkyl (C3-C6), alkenyl (C2-C6), alkynyl (C2-C6 ), aryl (C6-C10) and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, CN, N3, ORa, SRa, NRaRb, -C (=O)NRaRb, alkyl (C1-C6), haloalkyl (C1-C6), alkynyl (C2C6), aryl (C6-C10) and 5- to 10-membered heteroaryl.

[00108] In another embodiment, R1 is H, D, Cl, CH3, CH2CH3, CF3, CH2CF3, OCH3, OCH2CH3, NH2, NHCH3 or N(CH3)2, provided that when each of W1, W2 and W3 is CH, R1 is not H or NH2.

[00109] In another embodiment, each Rc is independently H, D, F, Cl, N3, CN, NH2, alkyl (C1-C3), alkoxy (C1-C3), alkyl (C1-C3) amino, cycloalkyl (C3-C6) or heterocyclyl (C3-C6), wherein each of alkyl (C1-C3), alkoxy (C1-C3), alkyl (C1-C3) amino, cycloalkyl (C3-C6) and heterocyclyl ( C3-C6) is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, CN, N3, OH, NH2, alkyl (C1-C3), cycloalkyl (C3-C6) and haloalkyl (C1-C3 ).

[00110] Some non-limiting examples of the compounds disclosed herein are shown in the following: Table 1

[00111] The present invention also comprises the use of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the acutely or chronically treatment of a hyperproliferative disease state and/or an angiogenesis-mediated disease state , including those described above. The compounds disclosed herein are useful in the manufacture of an anti-cancer drug. The compounds disclosed herein are also useful in the manufacture of a medicament for alleviating or preventing disorders through inhibition of protein kinases. The present invention comprises a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) in association with at least one pharmaceutically acceptable carrier, adjuvant or diluent.

The present invention also comprises a method of treating disorders related to hyperproliferation and angiogenesis in a subject having or susceptible to such a disorder, the method comprising treating the subject with a therapeutically effective amount of a compound of Formula (I).

[00113] Unless otherwise stated, all pharmaceutically acceptable stereoisomers, geometric isomers, tautomers, solvates, metabolites, salts, and prodrugs of the compounds disclosed herein are within the scope of the invention.

In certain embodiments, the salt is a pharmaceutically acceptable salt. The phrase "pharmaceutically acceptable" indicates that the substance or composition must be chemically and/or toxicologically compatible, with the other ingredients comprising a formulation, and/or with the mammal being treated therewith.

The compounds disclosed herein also include salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of Formula (I) and/or for separating enantiomers of compounds of Formula (I).

[00116] Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, for example, acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/ hydrochloride, chlortheophylonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, iodide/iodine, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulfate, nitrate, naphthoate octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, subsalicylate, tartrate, tosylate and trifluoroacetate.

Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[00118] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, acid benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[00119] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[00120] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include the ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins and the like. Certain organic amines include isopropylamine, benzathine, choline, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

[00122] The pharmaceutically acceptable salts of the present invention can be synthesized from a basic or acidic moiety by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as hydroxide, carbonate, bicarbonate or the like of Na, Ca, Mg, or K), or by reacting. take the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or an organic solvent, or a mixture of the two. In general, the use of non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. Lists of additional suitable salts can be found, for example, in "Remingtons Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[00123] Furthermore, the compounds disclosed herein, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization. The compounds disclosed herein may inherently or intentionally form solvates with pharmaceutically acceptable solvents (including water); therefore, the invention is intended to cover both solvated and unsolvated form.

[00124] In another aspect, methods of preparing, methods of separating, and methods of purifying compounds of Formula (I) are provided herein. The compounds disclosed herein may generally have several asymmetric centers and are typically represented as racemic mixtures. This invention is intended to encompass racemic mixtures, partially racemic mixtures and separate enantiomers and diastereomers.

[00125] The compounds disclosed herein may be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof. This invention is intended to encompass mixtures of isomers, rotamers, atropisomers, tautomers, isomers, rotamers, atropisomers, or partially mixed tautomers, and separate isomers, rotamers, atropisomers, tautomers.

[00126] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have the structures represented by the formulas given here except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2H, 3H, 11C, 13C, 14C, 15N 18F 31P 32P 36S 37 Cl and 125I respectively.

[00127] In another aspect, the compounds disclosed herein include isotopically labeled compounds as defined herein, for example those in which radioactive isotopes such as 3H, 14C and 18F, or those in which non-radioactive isotopes such as 2H and 13C are gifts. Such isotopically labeled compounds are useful in metabolic studies (with 14C), reaction kinetic studies (with eg 2H or 3H), detection or imaging techniques such as positron emission tomography (PET) or computed tomography photon emission assays (SPECT) including drug or substrate tissue distribution assays, or in the radioactive treatment of patients. In particular, an 18F or labeled compound may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of Formula (I) in general may be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically labeled reagent in place of the previously used unlabelled reagent.

[00128] Furthermore, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D) may provide certain therapeutic advantages that result from increased metabolic stability, for example increased in vivo half-life or decreased dosage requirements or a improvement in the therapeutic index. It is understood that deuterium in this context is considered to be a substituent of a compound of formula (I). The concentration of such a heavier isotope, specifically deuterium, can be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio of isotopic abundance to the natural abundance of a specified isotope. If a substituent in a compound of this invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% incorporation of deuterium in each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation) , or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates in accordance with the invention include those in which the solvent of crystallization may be isotopically substituted, for example D2O, acetone-d6, and DMSO-d6.

COMPOSITION, FORMULATIONS AND MANAGEMENT OF THE COMPOUNDS DISCLOSED HERE

[00129] According to one aspect, the invention describes pharmaceutical compositions which include a compound of Formula (I), a compound listed in Table 1, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in the compositions disclosed herein is such that it is effective to detectably inhibit a protein kinase in a biological sample or in a patient.

[00130] It will also be appreciated that certain of the compounds disclosed herein may exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. In accordance with the present invention, a pharmaceutically acceptable derivative includes, but is not limited to, prodrugs, salts, esters, salts of such esters, or any other pharmaceutically acceptable adduct or derivative which upon administration to a patient in need is capable of to provide, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.

[00131] As described above, the pharmaceutically acceptable compositions of the invention disclosed herein further comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other vehicle, dispersion or suspension aids. liquids, surface active agents, isotonic agents, thickeners or emulsifying agents, preservatives, solid binders, lubricants and the like, as suitable for the particular dosage form desired. In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boilan, 1988-1999, Marcel Dekker, New York, the contents of each of which are incorporated herein by reference, various carriers used in formulating pharmaceutically acceptable compositions and known techniques for preparing the same are disclosed. Except to the extent that any conventional carrier medium is incompatible with the compounds disclosed herein, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition , its use is considered to be within the scope of this invention.

[00132] Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine , sorbic acid or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica , magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; baby powder; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, saffron oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline solution; Anler's solution; ethyl alcohol, and phosphate buffer solutions, as well as other compatible non-toxic lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants they may also be present in the composition, at the discretion of the formulator.

The compositions disclosed herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasal, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intraocular, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention can be aqueous or oleaginous suspension. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Anler's solution, and isotonic sodium chloride solution. Furthermore, sterile fixed oils are conventionally used as a solvent or suspending medium.

[00134] For this purpose, any bland fixed oil can be used including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated versions. These oily solutions or suspensions may also contain a long chain alcoholic diluent or dispersant such as carboxymethyl cellulose or similar dispersing agents which are commonly used in formulating pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans, and other emulsifying agents or bioavailability enhancers that are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation purposes.

The pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifiers and suspending agents. If desired, certain sweetening, flavoring or coloring agents can also be added.

Alternatively, the pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eyes, skin, or lower intestinal tract. Suitable topical formulations are easily prepared for each of these areas or organs.

[00138] Topical application to the lower intestinal tract can be carried out in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically transdermal patches can also be used. For topical applications, pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for the topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[00139] For ophthalmic use, pharmaceutically acceptable compositions can be formulated, for example, as micronized suspensions in isotonic solution, pH-adjusted sterile saline or other aqueous solution, or, preferably, as solutions in isotonic, sterile-adjusted saline solution at pH or other aqueous solution, with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, pharmaceutically acceptable compositions may be formulated in an ointment such as petroleum jelly. The pharmaceutically acceptable compositions of this invention can also be administered by nasal aerosol or inhalation. Such compositions are prepared in accordance with techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline, using benzyl alcohol or other suitable preservative, absorption enhancers to enhance bioavailability, fluorocarbons, and/or other solubilizing agents or conventional dispersion.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, peanut, corn, wheat germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol , polyethylene glycols and sorbitan fatty acid esters, and mixtures thereof. In addition to inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Anler's solution, U.S.P. and isotonic sodium chloride solution. Furthermore, sterile, fixed oils are conventionally used as a solvent or suspending medium. For this purpose any bland fixed oil can be used including synthetic mono- or diglycerides. Also, fatty acids such as oleic acid are used in the preparation of injectables.

[00142] Injectable formulations can be sterilized, for example, by filtration through a bacterial retention filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium before of use. In order to prolong the effect of a compound disclosed herein, it is often desirable to delay absorption of the compound from subcutaneous or intramuscular injections. This can be accomplished by using a liquid suspension of crystalline or amorphous material with insufficient water solubility. The compound's absorption rate then depends on its dissolution rate which, in turn, may depend on the crystal size and crystalline form. Alternatively, dissolving or suspending the compound in an oil vehicle effects delayed absorption of a parenterally administered form of the compound.

[00143] The injectable depot forms are manufactured by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the compound to polymer ratio and the nature of the particular polymer used, the rate of compound release can be controlled. Some non-limiting examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at temperature environment but liquids at body temperature and therefore fuse in the rectum or vaginal cavity and release the active compound.

[00145] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one pharmaceutically acceptable inert excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) wetting agents such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, starch of potato or tapioca, alginic acid, certain silicates, and sodium carbonate, e) solution of retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, alcohol cetyl and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, lauryl sodium sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form can also comprise buffering agents.

[00146] Solid compositions of a similar type can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, pills, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Some non-limiting examples of embedding compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one or more excipients as mentioned above. Solid dosage forms of tablets, pills, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release control coatings and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, for example, tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms can also comprise buffering agents. They may optionally contain soothing agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Some non-limiting examples of embedding compositions which can be used include polymeric substances and waxes.

Dosage forms for the topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any of the necessary preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also considered to be within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled release of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

The compounds disclosed herein are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The term "dosage unit form" as used herein refers to a physically separate unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily use of the compounds and compositions disclosed herein will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend on a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and excretion rate of the specific compound used; duration of treatment; drugs used in combination or coincidental with the specific compound used, and similar factors well known in the medical arts.

The amount of the compounds of the present invention that can be combined with the carrier materials to produce a composition in a single dosage form will vary depending on the host treated and the particular mode of administration. Preferably, the compositions should be formulated so that a dosage of between 0.01 and 200 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.

The compounds of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other therapeutic (pharmaceutical) agents where the combination does not cause any unacceptable adverse effects. This may be of particular relevance to the treatment of hyper-proliferative diseases such as cancer. In this case, the compound of this invention can be combined with known cytotoxic agents, signal transduction inhibitors, or with other anti-cancer agents, as well as mixtures and combinations thereof. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as "appropriate for the disease, or condition, that is being treated". As used herein, "additional therapeutic agents" is intended to include chemotherapeutic agents and other antiproliferative agents.

[00152] For example, chemotherapeutic agents or other anti-proliferative agents can be combined with the compounds of this invention to treat proliferative disease or cancer. Examples of chemotherapeutic agents or other antiproliferative agents include HDAC inhibitors including, but not limited to, SAHA, MS-275, MGO 103, and those described in WO 2006/010264, WO 03/024448, WO 2004/069823, US 2006/0058298, US 2005/0288282, WO 00/71703, WO 01/38322, WO 01/70675, WO 03/006652, WO 2004/035525, WO 2005/030705, WO 2005/092899, and demethylating agents including, but not limited to, not limited to, 5-aza-dC, Vidaza and Decitabine and those described in US 6,268137, US 5,578,716, US 5,919,772, US 6,054,439, US 6,184,211, US 6,020,318, US 6,066,625, US 6,506,735, US 6,221,849, US 6,953,783, US 11/393,380.

[00153] In another embodiment of the present invention, for example, chemotherapeutic agents or other anti-proliferative agents may be combined with the compounds of this invention to treat proliferative diseases and cancer. Examples of known chemotherapeutic agents include, but are not limited to, for example, other anti-cancer therapies or agents that can be used in combination with the inventive anti-cancer agents of the present invention and include surgery, radiation therapy (in some examples, gamma radiation, radiation therapy of neutron beam, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes, to name a few), endocrine therapy, taxanes (paclitaxel, taxotere), platinum derivatives (cisplatin, carboplatin, oxaliplatin), modifiers of biological response (interferons, interleukins), tumor necrosis factor (TNF, agents that target the TRAIL receptor, to name a few), hyperthermia and cryotherapy, agents to mitigate any adverse effects (eg, antiemetics), and other medications approved chemotherapeutics, including, but not limited to, alkylating drugs (chlormethine, chlorambucil, cyclophosphamide, i. phosphamide, melphalan, etc.), anti-metabolites (methotrexate, raltitrexed, pemetrexed, etc), purine antagonists and pyrimidine antagonists (6-mercaptopurine, 5-fluorouracil, cytarabine, gemcitabine), antifuse poisons (vinblastine, vincristine, vinorelbine) , podophyllotoxins (etoposid, irinotecan, topotecan), antibiotics (doxorubicin, bleomycin, mitomycin), nitrosoureas (carmustine, lomustine), cell cycle inhibitors (KSP mitotic kinesin inhibitors, CENP-E and CDK inhibitors), enzymes (asparaginase) , hormones (tamoxifen, leuprolide, flutamide, megestrol, dexamethasone), antiangiogenic agents (avastin and others), monoclonal antibodies (Belimumab (BENLYSTA®), brentuximab (ADCETRIS®), cetuximab (ERBITUX®), gentuzumab (MILOTARG®), ipilimumab (YERVOY®), ofatumumab (ARZERRA®), panitumumab (VECTIBIX®), ranibizumab (LUCENTIS®), rituximab (RITUXAN®), tositumomab (BEXXAR®), trastuzumab (HERCEPTIN®), kinase inhibitors (imatinib (GLEEVEC®) , sunitinib (SUTENT®), sorafe nib (NEXAVAR®), cetuximab (ERBITUX®), trastuzumab (HERCEPTIN®), erlotinib (TARCEVA®), gefitinib (IRESSA®), dasatinib (SPRYCEL®), nilotinib (TASIGNA®), lapatinib (TYKERB®), crizotinib ( XALKORI®), ruxolitinib (JAKAFI®), vemurafenib (ZELBORAF®), vandetanib (CAPRELSA®), pazopanib (VOTRIENT®), and others), and agents to inhibit or activate cancer pathways such as the mTOR, HIF (factor) pathways induced by hypoxia) (such as everolimus and tensirolimus) and others. For a more comprehensive discussion of updated cancer therapies see, http://www.nci.nih.gov/, a list of FDA-approved oncology drugs at http://www.fda.gov/cder/cancer/ druglist-rame.htm, and The Merck Manual, Eighteenth Ed. 2006, the entire contents of which are hereby incorporated by reference.

[00154] In another embodiment, the compounds disclosed herein may be combined with cytotoxic anti-cancer agents. Some non-limiting examples of such agents can be found in the 13th Edition of the Merck Index (2001). These agents include, by no means of limitation, asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycin), epirubicin, etoposide, 5-fluoromethylamine -urea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifene, streptozocine, tamoxifene, thiovincricanine, guanine.

[00155] Other cytotoxic drugs suitable for use with the compounds disclosed herein include, but are not limited to, those compounds known to be used in the treatment of neoplastic diseases, such as those for example in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition, 1996, McGraw-Hill). These agents include, by no means of limitation, aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine, cladribine, busulfan, diethylstilbestrol, 2,2O-difluorodeoxycytidine, docetaxel, erythrohydroxynonyladenine, ethinyl estradiol, 5-fluorodeoxyuridine, 5-monofluorophosphate fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, pentostatin, N-phosphonoacetyl-1-aspartate (PALA), plicamycin, semustine , testosterone propionate, thiotepa, trimethylmelamine, uridine, and vinorelbine.

Other cytotoxic anticancer agents suitable for use in combination with the compounds disclosed herein also include newly discovered cytotoxic principles such as oxaliplatin, gemcitabine, capecitabine, epothilone and its natural or synthetic derivatives, temozolomide (Quinn et al., J. Clin. Oncology, 2003, 21(4), 646-651), tositumomab (Bexxar®), trabedectin (Vidal et al., Proceedings of the American Society for Clinical Oncology 2004, 23, abstract 3181), and protein inhibitors of Eg5 kinesin fusion (Wood, et al. Curr. Opin. Pharmacol., 2001, 1, 370377).

[00157] In another embodiment, the compounds disclosed herein can be combined with other signal transduction inhibitors. Some non-limiting examples of such agents include antibody therapies such as trastuzumab (HERCEPTIN®), cetuximab (ERBITUX®), ipilimumab (YERVOY®) and pertuzumab. Examples of such therapies also include, by no means of limitation, small molecule kinase inhibitors such as imatinib (GLEEVEC®), sunitinib (SUTENT®), sorafenib (NEXAVAR®), erlotinib (TARCEVA®), gefitinib (IRESSA® ), dasatinib (SPRYCEL®), nilotinib (TASIGNA®), lapatinib (TYKERB®), crizotinib (XALKORI®), ruxolitinib (JAKAFI®), vemurafenib (ZELBORAF®), vandetanib (CAPRELSA®), pazopanib (VOTRIENT®), afatinib, alisertib, amuvatinib, axitinib, bosutinib, brivanib, canertinib, cabozantinib, cediranib, crenolanib, dabrafenib, dacomitinib, danusertib, dovitinib, foretinib, ganetespib, ibrutinib, cediranib, innitinib, niraparib, oprozomib, olaparib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, saracatinib, saridegib, tandutinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, vertibanib, MS, vitalipib, 76, trametinib, 76 JNJ38877605, TKI2 58, GDC-0941 (Folkes, et al., J. Med. Chem., 2008, 51: 5522), BZE235, et al.

[00158] In another embodiment, the compounds disclosed herein can be combined with histone deacetylase inhibitors. Some non-limiting examples of such agents include suberoylanilide hydroxamic acid (SAHA), LAQ-824 (Ottmann, et al. Proceedings of the American Society for Clinical Oncology 2004, 23, abstract 3024), LBH-589 (Beck, et al. Proceedings of the American Society for Clinical Oncology 2004, 23, abstract 3025), MS-275 (Ryan, et al. Proceedings of the American Association of Cancer Research 2004, 45, abstract 2452), FR-901228 (Piekarz, et al. Proceedings of the American Society for Clinical Oncology 2004, 23, abstract 3028) and MGCDOl 03 (US 6,897,220).

In another embodiment, the compounds disclosed herein can be combined with other anti-cancer agents such as proteasome inhibitors, and mTOR inhibitors. These include, by no means of limitation, bortezomib, and CCI-779 (Wu, et al., Proceedings of the American Association of Cancer Research 2004, 45, abstract 3849). The compounds disclosed herein can be combined with other anti-cancer agents such as topoisomerase inhibitors, including but not limited to camptothecin.

These additional agents may be administered separately from the compound-containing composition as part of a multiple dosage regimen. Alternatively, these agents may be part of a single dosage form, mixed together with the compound of this invention in a single composition. If administered as part of a multiple dosage regimen, the two active agents can be subjected simultaneously, sequentially, or within a time period of one another that would result in the desired activity of the agents.

The amount of both the compound and the additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that can be combined with the carrier materials to produce a single dosage form will vary depending on the host treated and the particular manner administration. Typically, the amount of additional therapeutic agent present in the compositions of this invention will not be greater than the amount that would normally be administered in a composition comprising this therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising this agent as the only therapeutically active agent. In those compositions which comprise an additional therapeutic agent, this additional therapeutic agent and the compound of this invention may act synergistically.

USES OF THE COMPOUNDS AND COMPOSITIONS DISCLOSED HERE

The invention describes pharmaceutical compositions which include a compound of Formula (I), or a compound listed in Table 1, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in the compositions disclosed herein is such that it is effective to detectably inhibit or modulate a protein kinase, such as PI3K or mTOR activity. The compounds disclosed herein are useful in therapy as anti-cancer agents or to minimize deleterious effects of PI3K or mTOR signaling.

The compounds disclosed herein would be useful, but not limited to, for preventing or treating a proliferative disease, condition, or disorder in a patient by administering to the patient a compound or composition disclosed herein in an effective amount. Such diseases, conditions, or disorders include cancer, particularly metastatic cancer, atherosclerosis, and pulmonary fibrosis.

The compounds disclosed herein would be useful for the treatment of neoplasm including cancer and metastasis, including, but not limited to: carcinoma such as cancer of the bladder, breast, colon, kidney, liver, lung (including small cell lung cancer) , esophagus, gallbladder, ovary, pancreas, stomach, neck, thyroid, prostate, and skin (including squamous cell carcinoma); hematopoietic tumors of lymphoid lineage (including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkett's lymphoma); hematopoietic tumors of myeloid lineage (including acute and chronic myelogenous leukemias, myelodysplastic syndrome, and promyelocytic leukemia); tumors of mesenchymal origin (including fibrosarcoma and rhabdomyosarcoma, and other sarcomas, for example of soft tissue and bone); central and peripheral nervous system tumors (including astrocytoma, neuroblastoma, glioma, and schvanomas); and other tumors (including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderoma pigmentosum, keratoctantoma, thyroid follicular cancer, and Kapose's sarcoma).

The compounds would also be useful for the treatment of ophthalmologic conditions such as corneal graft rejection, ocular neovascularization, retinal neovascularization including neovascularization following injury or infection, diabetic retinopathy, retrolental fibroplasia and neovascular glaucoma; retinal ischemia; vitreous hemorrhage; ulcerative diseases such as gastric ulcer; pathological, but not malignant, conditions such as hemangiomas, including infantile hemaginoma, nasopharyngeal angiofibroma, and avascular bone necrosis; and disorders of the female reproductive system such as endometriosis. The compounds are also useful for treating edema, and vascular hyperpermeability conditions.

The compounds disclosed herein are also useful in the treatment of diabetic conditions such as diabetic retinopathy and microangiopathy. The compounds disclosed herein are also useful in reducing blood flow to a tumor in an individual. The compounds disclosed herein are also useful in reducing tumor metastasis in an individual.

[00167] In addition to being useful for human treatment, these compounds are also useful for veterinary treatment of pets, exotic animals and farm animals, including mammals, rodents, and the like. The most preferred animals include horses, dogs, and cats. As used herein, the compounds disclosed herein include the pharmaceutically acceptable derivatives thereof.

[00168] Where the plural form is used for compounds, salts, and the like, this is also taken to mean a single compound, salt and the like.

The method of treatment which includes administering a compound or composition disclosed herein may further include administering to the patient an additional therapeutic agent (combination therapy) selected from: a chemotherapeutic or anti-proliferative agent, or an anti-inflammatory agent, wherein the therapeutic agent additional is appropriate for the disease being treated and the additional therapeutic agent is administered together with a compound or composition disclosed herein as a single dosage form or separately from the compound or composition as part of a multiple dosage form. The additional therapeutic agent can be administered at the same time as a compound disclosed herein or at a different time. In the latter case, administration may be staggered, for example, over 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, or 2 months.

The invention also describes a method of inhibiting the growth of a cell expressing PI3K or mTOR, which includes contacting the cell with a compound or composition disclosed herein, thereby causing inhibition of cell growth. Some non-limiting examples of a cell whose growth can be inhibited include: a breast cancer cell, a colorectal cancer cell, a lung cancer cell, a papillary carcinoma cell, a prostate cancer cell, a lymphoma cell, a colon cancer cell, pancreatic cancer cell, ovarian cancer cell, cervical cancer cell, central nervous system cancer cell, osteogenic sarcoma cell, renal carcinoma cell, hepatocellular carcinoma cell , a bladder cancer cell, a gastric carcinoma cell, a head and neck squamous cell carcinoma, a melanoma cell, or a leukemia cell.

The invention provides a method of inhibiting or modulating PI3K or mTOR activity in a biological sample comprising contacting the biological sample with a compound or composition disclosed herein. The term "biological sample" as used herein means a sample outside of a living organism and includes, without limitation, cell cultures or extracts thereof; biopsy material obtained from a mammal or extracts from it; and blood, saliva, urine, feces, semen, tears, or other bodily fluids or extracts thereof. Inhibition or modulation of kinase activity, particularly PI3K or mTOR activity, in a biological sample is useful for a variety of purposes known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological specimen storage, and biological assays.

In certain embodiments of the present invention an "effective amount" or "effective dose" of the pharmaceutically acceptable compound or composition is that amount effective to treat or lessen the severity of one or more of the aforementioned disorders. The compounds and compositions according to the method of the present invention can be administered using any amount and any route of administration effective to treat or lessen the severity of the disorder or disease. The exact amount required will vary from individual to individual depending on the species, age, and general condition of the individual, the severity of the infection, the particular agent, its mode of administration, and the like. A compound or composition can also be administered with one or more other therapeutic agents, as discussed above.

The compounds of this invention or pharmaceutical compositions thereof can also be used to coat an implantable medical device such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of vessels after injury). However, patients using stents or other implantable devices are at risk for clot formation or platelet activation. These undesirable effects can be prevented or mitigated by precoating the device with a pharmaceutically acceptable composition comprising a compound of this invention.

Suitable coatings and general preparation of coated implantable devices are described in U.S. Patent Nos. 6,099,562; 5,886,026; and 5,304,121, the contents of each of which are incorporated herein by reference. Coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings can optionally be further covered by a suitable topcoat of fluorosilicon and, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition. Implantable devices coated with a compound of this invention are another embodiment of the present invention. Compounds can also be coated onto implantable medical devices, such as beads, or co-formulated with a polymer or other molecule, to provide a "drug depot" thus allowing the drug to be released in a longer period of time than administering an aqueous solution of the drug.

GENERAL SYNTHETIC PROCEDURES

[00175] In order to illustrate the invention, the following examples are included. However, it is to be understood that these examples do not limit the invention and are only intended to suggest a method of practicing the invention.

In general, the compounds in this invention can be prepared by the methods described herein, wherein the substituents are as defined for formula (I), above, except where otherwise mentioned. The following non-limiting schemes and examples are presented to further exemplify the invention. Persons skilled in the art will recognize that the chemical reactions described herein can be readily adapted to prepare various other compounds disclosed herein, and alternative methods for preparing the compounds of this invention are believed to be within the scope of this invention. For example, the synthesis of compounds not exemplified according to the invention can be successfully carried out by modifications evident to those skilled in the art, for example, by appropriately protecting interfering groups, by the use of other suitable reagents known in the art other than those described, and/or making routine modifications to the reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability to preparing other compounds disclosed herein.

[00177] In the examples described below, unless otherwise indicated all temperatures are given in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, Shanghai Medpep. Co Ltd, Aladdin-Shanghai Jinchun Reagents, Ltd, and have been used without further purification unless otherwise indicated. Common solvents were purchased from commercial suppliers such as Shantou Xilong Chemical Factory, Guangdong Guanghua Reagent Chemical Factory Co. Ltd., Guangzhou Reagent Chemical Factory, Tainjin YuYu Fine Chemical Ltd., Qingdao Tenglong Reagent Chemical Ltd., and Qingdao Ocean Chemical Factory.

Anhydrous THF, dioxane, toluene, and ether were obtained by refluxing the solvent with sodium. Anhydrous CH2Cl2 and CHCl3 were obtained by refluxing the solvent with CaH2. EtOAc, PE, hexanes, DMA and DMF were treated with anhydrous Na2SO4 prior to use.

[00179] The reactions shown below were generally carried out under a positive pressure of nitrogen or argon or with a drying tube (unless otherwise stated) in anhydrous solvents, and the reaction vials were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. The glassware was oven dried and/or heat dried. Column chromatography was conducted using a silica gel column. Silica gel (300 to 400 mesh) was purchased from Qingdao Ocean Chemical Factory. 1H NMR spectra were recorded with a Bruker 400 MHz spectrometer or a Bruker 600 MHz spectrometer at room temperature. 1H NMR spectra

[00180] were obtained as solutions of CDCl3, DMSO-d6, CD3OD or acetone-d6 (reported in ppm), using TMS (0 ppm) or chloroform (7.26 ppm) as the reference standard. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (enlarged), dd (doublet of doublets), dt (doublet of triplets). Binding constants, when given, are reported in Hertz (Hz).

[00181] Low resolution mass spectral (MS) data were generally determined on an Agilent 6120 Quadripolar HPLC-MS (Zorbax SB-C18, 2.1 x 30 mm, 3.5 microns, 6 minutes conduction, 0 0.6 ml/min flow rate, 5% to 95% (0.1 % formic acid in CH3CN) in (0.1 % formic acid in H2O)) with UV detection at 210 nm/254 nm and mode of electrospray ionization (ESI).

The purities of the compounds were evaluated by the Agilent 1260 Pre-HPLC or Calesep 250 Pre-HPLC Pump (NOVASEP column 50/80 mm DAC) with UV detection at 210 nm/254 nm.

[00183] The following abbreviations are used throughout the specification: ATP adenosine triphosphate AcOH, HOAc, CH3COOH acetic acid AIBN azodiisobutyronitrile BBr3 boron tribromide Bu4NF tetrabutylammonium fluoride BINAP 2,2O-bis(diphenylphosphino)-1,1O-binaphthyl BOC, Boc butyloxycarbonyl BSA bovine serum albumin n-BuOH butyl alcohol n-BuLi n-butyllithium CDCl3 deuterated chloroform CCl4 carbon tetrachloride CHCl3 chloroform CH2Cl2, DCM methylene chloride CH3SO2Cl, MsCl 4-toluene sulfonyl chloride, Mesc CN Carbonate Cs2CO3 acetonitrile CH3SO2Cl, MsCl methanesulfonyl chloride Cs2CO3 cesium carbonate CuI cuprous iodide DCC N,NO-Dicyclohexylcarbodie DAST diethylaminosulfur trifluoride DBU 1,8-Diazabicyclo[5,4,0]undec-7-ene DEAD azodicarboxyadicarboxylate dimethyl azodicarboxylate DIBAL diisobutylaluminum hydride DIEA, DIPEA, i-Pr2NEt diisopropylethylamine DMAP 4-dimethylaminopyridine DME dimethoxyethane DMF dimethylformamide DMSO sulfoxide of dimethyl DPPA diphenylphosphoryl azide EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EtOAc, EA ethyl acetate EtOH ethanol Et2O diethyl ether Et3N, TEA triethylamine FBS fetal bovine serum g gram h hour HATU O-(7-hexafluorophosphate) azabenzotriazol-1-yl)-N,N,NO,NO- tetramethyluronium HBr hydrobromic acid HBTU O-benzotriazol-1-yl-N,N,NO,NO-tetramethyluronium hexafluorophosphate H2O2 hydrogen peroxide HOAc,AcOH acetic acid HOBt hydrate of 1-hydroxy-benzotriazole i-Pr2NH diisopropylamine K2CO3 potassium carbonate KOAc, CH3COOK Potassium Acetate LiHMDS lithium bis(trimethylsilyl)amide LDA lithium diisopropylamide MCPBA meta-chloroperbenzoic acid MeI methyl iodide MeOH, CH3OH methanol 2-MetF methyl tetrahydrofuran MgSO4 magnesium sulfate MsCl methanesulfonyl chloride mL, ml milliliter N2 nitrogen NaBH4 sodium borohydride NaBH3CN sodium cyanoborohydride NaClO2 sodium chlorite NaH sodium hydride Na2CO3 sodium carbonate NaHCO3 sodium bicarbonate NaH2PO4 sodium biphosphate NaO(t-Bu) sodium tert-butoxide Na2SO4 sodium sulfate NBS N-Bromosuccinimide NIS N-Iodosuccinimide NH3 ammonia NH4Cl ammonium chloride NMP N-methylpyrrolidinium PBS phosphate-buffered saline P(t-Bu)3 tri(tert-butyl)phosphine Pd/C palladium on carbon Pd2(dba)3 bis(dibenzylideneacetone) palladium Pd(dppf)Cl2 1,1-bis(diphenylphosphino)ferrocene palladium palladium Pd(dppf)Cl2<H2Cl2 dichlorine adduct [1,rbis(diphenylphosphine)ferrocene] palladium(II) dichloromethane Pd(PPh3)4 palladium tetracis triphenylphosphine Pd(PPh3)2Cl2 Bis(triphenylphosphine)palladium(II) chloride PE petroleum ether (60 to 90 oC) POCl3 oxychloride phosphorus PCl5 phosphorus (V) chloride PyBop benzotriazol-1-yl-oxytripyrrolidinephosphonium hexafluorophosphate Pre-HPLC preparative high performance liquid chromatography RT, rt, rt room temperature Rt retention time TBAB tetrabutylammonium bromide TBAF tetrabutylammonium fluoride TBAHSO4 tetrabutylammonium hydrogen sulfate TBTU O-benzotriazol-1-yl-N,N,NO,NO-tetramethyluronium tetrafluoroborate TFA trifluoroacetic acid TEAC bis(tetra-carbonate) ethylammonium) THF tetrahydrofuran μl microliter X-Phos 5-Bromo-4-chloro-3-indolylphosphate p-Toluidine salt

Representative synthetic procedures for preparing compounds of the disclosure are outlined below in the following schemes. Unless otherwise indicated, R1, W1, W2, Y and Z carry the definitions given above in connection with formula (I). Rh is Cl, Br, or I. Scheme 1

[00185] Some compounds with structures as defined in Formula (I) can be prepared by a general method as illustrated in Scheme 1. The nitropyridine derivative (1) is converted to aminopyridine (2) under reducing condition such as hydrogenation in the presence of Pd/C catalyst or Fe powder under aqueous acidic conditions. Aminopyridine (2) is then coupled with sulfonyl chloride (3) to give the sulfonamide (4) in the presence of a base such as Na2CO3, Et3N, or pyridine in an aprotic solvent (eg, CH2Cl2, CHCl3, etc.), or in pyridine with a catalytic amount of DMAP, or under the Schotten-Baumann condition. Subsequent coupling of the sulfonamide (4) with bis(pinacolato)diboron (5) in the presence of an appropriate Pd catalyst leads to the boronic ester (6).

[00186] The synthesis of heteroaromatic core (12) having a bromine group is shown in Scheme 1. Bromoaryl (7) is first condensed with acetal (8) to provide bicyclic heteroaromatic (9) in an alcoholic solvent such as MeOH or EtOH. Subsequent iodination of (9) with N-iodosuccinimide at room temperature yields the iodine compound (10). Compound (10) is then coupled with acetylene, cyanide or azide Z (11) to give heteroaromatic compound (12) under basic conditions or in the presence of a Pd catalyst. Desired kinase inhibitors having formula (14) are obtained by coupling heteroaromatic bromine compound (12) with boronic ester (6) in the presence of an appropriate Pd catalyst. Scheme 2

Alternatively, the compounds disclosed herein can be prepared by the method as described in Scheme 2. The bromo compound (9) is first coupled with sulfonamide (6) to give the biaryl compound (15) using an appropriate Pd complex as a catalyst. The biaryl compound (15) is then treated with a halogenating agent (such as NIS) to produce compound (16). Coupling of compound (16) with compound (11) (i.e., acetylene, cyanide or azide derivatives) under basic conditions or in the presence of a Pd catalyst produces the desired kinase inhibitors (14). Scheme 3

Scheme 3 shows another method for preparing the kinase inhibitors disclosed herein. Thus, substituted heteroaryl compound (7) having a bromo group can react with 1,1-dimethoxy-N,N-dimethylmethanamine (17) at an elevated temperature to provide the enamine intermediate (18), which is further cyclized with halides. of alkyl (19) leading to nitrile (20). Linking the nitrile (20) with boronic ester (6) in the presence of an appropriate Pd catalyst provides the desired kinase inhibitors (21). Scheme 4

[00189] The compounds disclosed herein can also be prepared using the synthetic route as shown in Scheme 4. Thus, bromine substituted heteroaryl compound (7) is first cyclized with 2-chloroacetaldehyde (22) at an elevated temperature to give the compound (9). Coupling of compound (9) with boronic ester (6) in the presence of an appropriate Pd catalyst provides compound (23). Iodination of compound (23) with N-iodosuccinimide yields compound (24). Coupling of compound (24) with compound (11) (i.e., acetylene, cyanide or azide derivatives) under basic conditions or in the presence of a Pd catalyst produces the desired kinase inhibitors (14). Scheme 5

[00190] Some compounds with structures as defined in Formula (I) can also be prepared by a general method as illustrated in Scheme 5 above. Compound (25) is first treated with hydrazine hydrate (26) at an elevated temperature to provide compound (27), which is subsequently cyclized with diethoxymethoxyethane (28) leading to bicyclic heteroaromatic (29). Coupling the compound (29) with the boronic ester (6) in the presence of an appropriate Pd catalyst gives the compound (30). Bromination of compound (30) with N-bromosuccinimide yields compound (31). Coupling of compound (31) with compound (11) (i.e., acetylene, cyanide or azide derivatives) under basic conditions or in the presence of a Pd catalyst produces the desired kinase inhibitors (32). EXAMPLES Example 1 N-(5-(3-ethynimidazo[1,2-b]pyridazin-6-yl)-2-methoxypyridin-3-yl)-4-fluorobenzenesulfonamide

Step 1) 6-bromoimidazo[1,2-b]pyridazine

To a solution of 6-bromopyridazin-3-amine (3.48 g, 20 mmoles) in EtOH/H 2 O (5/1, 180 ml) was added 2-bromo-1,1-diethoxyethane (11.8 g, 60 mmoles), followed by p-toluenesulfonic acid (20.6 mg, 0.12 mmol). The mixture was stirred at 80°C for 16 hours and then concentrated in vacuo. The resulting solid was washed with H 2 O (4 ml), collected by filtration, and dried in a vacuum oven overnight at 40 °C to give the title compound as a gray solid (3.9 g, 100%). MS (ESI, pos. ion) m/z: 198.1 [M+H]+; 1 H-NMR (400 MHz, CDCl3): h 8.71 (d, J = 9.6 Hz, 1H), 8.44 (d, J = 1.6 Hz, 1H), 8.33 (d, J = 1 0.9 Hz, 1H), 7.97 (d, J = 9.6Hz, 1H).

Step 2) 6-bromo-3-iodoimidazo[1,2-b]pyridazine

To a solution of 6-bromoimidazo[1,2-b]pyridazine (1.98 g, 10.0 mmol) in methanol (50 ml) at -10 °C was added N-iodosuccinimide (2.47 g, 11.0 mmoles) in portions. The mixture was stirred at -10°C for 30 minutes and then allowed to warm to room temperature. The reaction was continued to stir at room temperature for 18 hours, then concentrated in vacuo. The residue was dissolved in 100 ml of DCM and washed with 50 ml of aqueous Na2CO3 solution. The organic phase was concentrated in vacuo to give the title compound as a pale yellow solid (2.0 g, 61%). MS (ESI, pos. ion) m/z: 323.9 [M+H]+; 1 H-NMR (400 MHz, CDCl 3 ): h 7.83 (s, 1H), 7.78 (d, J = 9.4 Hz, 1H), 7.21 (d, J = 9.4 Hz, 1H).

Step 3) 6-bromo-3-((trimethylsilyl)ethynyl)imidazo[1,2-b]pyridazine

[00193] To a suspension of 6-bromo-3-iodoimidazo[1,2-b]pyridazine (1.30 g, 4.0 mmol), ethynyltrimethylsilane (0.39 g, 4.0 mmol), Pd(PPh3 ) 2 Cl 2 (0.28 g, 0.4 mmol) and CuI (0.076 g, 0.4 mmol) in 1,4-dioxane (60 ml) was added DIPEA (2.6 g, 20.0 mmol). The resulting mixture was stirred at 90°C under N 2 atmosphere for 6 hours and then concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 3/1) to give the title compound as a yellow solid (385 mg, 33%). MS (ESI, pos. ion) m/z: 294.0 [M+H]+; 1 H-NMR (400 MHz, CDCl 3 ): h 7.93 (s, 1H), 7.80 (d, J = 9.4 Hz, 1H), 7.21 (d, J = 9.4 Hz, 1H), 0.32 (s, 9H).

Step 4) 4-fluoro-N-(2-methoxy-5-(3-((trimethylsilyl)ethynyl)imidazo[1,2-b]-pyridazin-6-yl)pyridine-3-yl)benzenesulfonamide

To a suspension of 4-fluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (472.9 mg, 1.17 mmol), 6-bromo-3-((trimethylsilyl)ethynyl)imidazo[1,2-b]pyridazine (309.0 mg, 1.1 mmol) and Pd(dppf)Cl2 ^CH2Cl2 (85.7 mg, 0.11 mmol) in 1,4-dioxane (30 mL) was added a solution of Na2CO3 (556.5 mg, 5.25 mmol) in water (6 mL). The mixture was stirred at 90°C under N2 atmosphere for 1 hour, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to give the title compound as white powder (260 mg, 50%) . MS (ESI, pos. ion) m/z: 496.0 [M+H]+; 1 H-NMR (400 MHz, CDCl3): h 8.56 (d, J = 2.2 Hz, 1H), 8.49 (d, J = 2.2 Hz, 1H), 8.02 (d, J = 9 .5 Hz, 1H), 8.00 (s, 1H), 7.91 (dd, J = 8.9 Hz, 5.0 Hz, 2H), 7.48 (d, J = 9.5 Hz, 1H), 7.14 (t, J = 8.5Hz, 2H), 7.00 (s, 1H), 3.93 (s, 3H), 0.33 (s, 9H).

Step 5) N-(5-(3-ethynimidazo[1,2-b]pyridazm-6-yl)-2-methoxypyridin-3-yl)-4-fluorobenzenesulfonamide

[00195] To a solution of 4-fluoro-N-(2-methoxy-5-(3-((trimethylsilyl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)pyridin-3-yl) benzenesulfonamide (180.0 mg, 0.36 mmol) in THF (15 ml) was added 0.73 ml of TBAF (0.73 mmol, 1.0 M in THF). The resulting mixture was stirred at room temperature for 30 minutes and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (PE/EtOAc (v/v) = 1/3) to give the title compound as a pale yellow solid (74.5 mg, 48%). MS (ESI, pos. ion) m/z: 424.1 [M+H]+; 1 H-NMR (400 MHz, DMSO-d6): h 8.68 (d, J = 2.2Hz, 1H), 8.31 (d, J = 2.2Hz, 1H), 8.28 (d, J = 9 0.6 Hz, 1H), 8.14 (s, 1H), 7.95 (d, J = 9.6 Hz, 1H), 7.91 (dd, J = 8.9Hz, 5.2 Hz, 2H ), 7.41 (t, J = 8.8Hz, 2H), 5.11 (s, 1H), 3.77 (s, 3H); 13C NMR (100 MHz, DMSO-d6): h 149.2, 142.0, 138.9, 138.5, 136.4, 130.0, 129.9, 129.1, 126.4, 124, 4, 121.2, 117.1, 116.5, 116.3, 111.8, 90.1, 70.1, 53.9. Example 2 4-fluoro-N-(5-(3-(3-hydroxyprop-1-yn-1-yl)imidazo[1,2-b]pyridazin-6-yl)-2-methoxypyridin-3-yl) benzenesulfonamide

Step 1) 3-(6-bromoimidazo[1,2-b]pyridazin-3-yl)prop-2-yn-1-ol

To a suspension of 6-bromo-3-iodoimidazo[1,2-b]pyridazine (1.48 g, 4.6 mmol), Pd(PPh3)2Cl2 (322 mg, 0.46 mmol), CuI (87mg, 0.46mmol) and triethylamine (2.33g, 23mmol) in DMF (65ml) was added prop-2-yn-1-ol (235mg, 4.2mmol). The mixture was stirred at room temperature under N2 atmosphere for 4 hours and concentrated in vacuo. The residue was diluted with brine (150 ml) and extracted with EtOAc (60 ml x 3). The combined organic phases were dried over anhydrous Na2SO4, then concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 4/1) to give the title compound as a yellow solid (580 mg, 50%). MS (ESI, pos. ion) m/z: 252.1 [M+H]+.

Step 2) 4-fluoro-N-(5-(3-(3-hydroxyprop-1-m-1-yl)imidazo[1,2-b]pyridazin-6-yl)-2-methoxypyridin-3-yl )benzenesulfonamide

[00197] To a suspension of 3-(6-bromoimidazo[1,2-b]pyridazin-3-yl)prop-2-yn-1-ol (500 mg, 2 mmoles), 4-fluoro-N-( 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (900 mg, 2.2 mmol) and Pd(dppf) ClrCH2Cl2 (164 mg, 0.2 mmol) in DME (40 ml) was added a solution of Na2CO3 (530 mg, 5 mmol) in H2O (4 ml). The mixture was stirred at 70°C under N 2 atmosphere for 4 hours, then cooled to room temperature, quenched with water (50 ml), and extracted with EtOAc (100 ml x 3). The combined organic phases were washed with brine (80 ml x 3), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 30/1) to give the title compound as a yellow solid (110 mg, 12%). MS (ESI, pos. ion) m/z: 454.0 [M+H]+; 1 H-NMR (400 MHz, DMSO-d6): h 3.74 (s, 3H), 4.49 (d, J = 5.9 Hz, 2H), 5.55 (t, J = 5.9 Hz, 1H ), 7.42 (t, J = 8.8 Hz, 2H), 7.87-7.92 (m, 3H), 8.09 (s, 1H), 8.27 (d, J = 9. 6 Hz, 1H), 8.33 (d, J = 2.2 Hz, 1H), 8.68 (d, J = 2.2 Hz, 1H), 10.19 (s, 1H). Example 3 4-fluoro-N-(5-(3-(3-hydroxybut-1-m-1-yl)imidazo[1,2-b]pyridazm-6-yl)-2-methoxypyridm-3-yl) benzenesulfonamide

Step 1) 4-(6-bromoimidazo[1,2-b]pyridazin-3-yl)but-3-yn-2-ol

To a suspension of 6-bromo-3-iodoimidazo[1,2-b]pyridazine (520 mg, 1.6 mmol), Pd(PPh3)2Cl2 (112 mg, 0.16 mmol), CuI (30 mg, 0.16 mmol) and DIPEA (1.04 g, 4.0 mmol) in DMF (24 ml) was added but-3-yn-2-ol (112 mg, 1.6 mmol). The resulting mixture was stirred at room temperature under N2 atmosphere for 2 hours and then concentrated in vacuo. The residue was purified by flash silica gel column chromatography (PE/DCM (v/v) = 1/50) to give the title compound as a yellow solid (210 mg, 50%). MS (ESI, pos. ion) m/z: 266.0 [M+H]+.

Step 2) 4-fluoro-N-(5-(3-(3-hydroxybut-1-m-1-yl)imidazo[1,2-b]pyridazm-6-yl)-2-methoxypyridin-3-yl )benzenesulfonamide

To a suspension of 4-fluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (354 mg, 0.87 mmol), 4-(6-bromoimidazo[1,2-b]pyridazin-3-yl)but-3-yn-2-ol (210 mg, 0.79 mmol) and Pd( dppf)ClrCH2Cl2 (58 mg, 0.08 mmol) in DMF (21 ml) was added a solution of Na2CO3 (210 mg, 1.97 mmol) in water (4 ml). The mixture was stirred at 70°C under N 2 atmosphere for 4 hours, then cooled to room temperature, quenched with H 2 O (100 ml), and extracted with EtOAc (100 ml x 3). The combined organic phases were concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v) = 100/1) to give the title compound as a light brown solid (149 mg, 40%). MS (ESI, pos. ion) m/z: 468.0 [M+H]+; 1 H-NMR (400 MHz, CDCl 3 ): h 10.17 (s, 1H), 8.70-8.69 (d, J = 2.2 Hz, 1H), 8.40-8.39 (d, J = 2.2 Hz, 1H), 8.28-8.26 (d, J = 9.5 Hz, 1H), 8.07 (s, 1H), 7.93-7.86 (m, 3H), 7.43-7.39 (t, J = 8.5 Hz, 2H), 5.67-5.66 (d, J = 5.4 Hz, 1H), 4.79-4.76 (m, 1H), 3.74 (s, 3H), 1.51-1.50 (d, J = 6.6 Hz, 3H). Example 4 4-fluoro-N-(5-(3-(3-hydroxy-3-methylbut-1-m-1-yl)imidazo[1,2-b]-pyridazm-6-yl)-2-methoxypyridm -3-yl)benzenesulfonamide

Step 1) 4-(6-bromoimidazo[1,2-b]pyridazin-3-yl)-2-methylbut-3-yn-2-ol

[00200] To a suspension of 6-bromo-3-iodoimidazo[1,2-b]pyridazine (1.0 g, 3.0 mmol), Pd(PPh3)2Cl2 (0.2 g, 0.3 mmol) , CuI (0.1 g, 0.6 mmol) and triethylamine (1 ml, 6 mmol) in DMF (15 ml) was added 2-methylbut-3-yn-2-ol (0.25 g, 3 mmol) . The mixture was stirred at room temperature under N 2 atmosphere for 5 hours, then quenched with H 2 O (40 ml), and extracted with EtOAc (30 ml x 3). The combined organic phases were washed with brine (100 ml), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give the title compound as a yellow solid (0.5 g, 58%). MS (ESI, pos. ion) m/z: 280.0 [M+H]+.

Step 2) 4-fluoro-N-(5-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)imidazo[1,2-b]-pyridazm-6-yl)-2- methoxypyridm-3-yl)benzenesulfonamide

To a suspension of 4-(6-bromoimidazo[1,2-b]pyridazin-3-yl)-2-methylbut-3-yn-2-ol (0.36 g, 1.3 mmol), 4-fluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (0.52 g, 1 0.3 mmol) and Pd(dppf)Cl2^CH2Cl2 (0.1 g, 0.13 mmol) in DME (20 ml) was added a solution of Na2CO3 (0.28 g, 2.6 mmol) in H2O (1 .4 ml). The mixture was stirred at 100°C under a N 2 atmosphere overnight and then concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/2) to give the title compound as a yellow solid (0.4 g, 64%). MS (ESI, pos. ion) m/z: 482.0 [M+H]+; 1 H-NMR (400 MHz, CDCl 3 ): h 10.15 (s, 1H), 8.73 (d, J = 2.1 Hz, 1H), 8.46 (d, J = 2.1 Hz, 1H), 8.28 (d, J = 9.5 Hz, 1H), 8.07 (s, 1H), 7.95 (d, J = 9.5 Hz, 1H), 7.87-7.84 (m , 2H), 7.43-7.39 (m, 2H), 3.73 (s, 3H), 1.58 (s, 6H). Example 5 4-fluoro-N-(2-methoxy-5-(3-(prop-1-yn-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyridin-3-yl)benzenesulfonamide

Step 1) 6-bromo-3-(prop-1-in-1-yl)imidazo[1,2-b]pyridazine

To a suspension of 6-bromo-3-iodoimidazo[1,2-b]pyridazine (747 mg, 2.31 mmol), Pd(PPh3)2Cl2 (161.5 mg, 0.23 mmol), CuI (44 mg, 0.23 mmol) and DIPEA (1.49 g, 11.55 mmol) in DMF (35 ml) was added Propine (about 3% in Heptane) (20 ml, 4.44 mmol). The mixture was stirred at room temperature under N 2 atmosphere for 2 hours, then quenched with H 2 O (100 ml), and extracted with EtOAc (100 ml x 3). The combined organic phases were concentrated in vacuo. The residue was purified by flash silica gel column chromatography (pure DCM) to give the title compound as a yellow solid (400 mg, 73.6%). MS (ESI, pos. ion) m/z: 236.0 [M+H]+.

Step 2) 4-fluoro-N-(2-methoxy-5-(3-(prop-1-yn-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyridin-3-yl) benzenesulfonamide

To a suspension of 6-bromo-3-(prop-1-yn-1-yl)imidazo[1,2-b]-pyridazine (400 mg, 1.70 mmol) in DMF (30 ml) was 1\](X]ppf)ClyCl I2Cl2 (125 mg, 0.17 mmol) is added. The mixture was stirred at room temperature under N2 atmosphere for 0.5 hour. A solution of 4-fluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-benzenesulfonamide (760 mg , 1.86 mmol) in DMF (15 ml) was added to the reaction mixture, followed by the addition of a solution of Na2CO3 (450 mg, 4.25 mmol) in H2O (11 ml). The resulting mixture was stirred at 70°C under N 2 atmosphere for 4 hours, then cooled to room temperature, quenched with H 2 O (100 ml), and extracted with EtOAc (100 ml x 3). The combined organic phases were concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v) = 200/1) to give the crude product as a brown solid. The solid was washed with H 2 O (10 ml), followed by EtOH (5 ml) to give the title compound as a light brown solid (262 mg, 35.3%). MS (ESI, pos. ion) m/z: 438.1 [M+H]+; 1 H-NMR (400 MHz, CDCl 3 ): h 10.18 (s, 1H), 8.67 (d, J = 2.2 Hz, 1H), 8.35 (d, J = 2.2 Hz, 1H), 8.24 (d, J = 9.5 Hz, 1H), 8.01 (s, 1H), 7.89-7.86 (m, 3H), 7.41 (t, J = 8.5 Hz , 2H), 3.75 (s, 3H), 2.26 (s, 3H). Example 6 N-(5-(3-cyanoimidazo[1,2-b]pyridazin-6-yl)-2-methoxypyridin-3-yl)-4-fluorobenzenesulfonamide

Step 1) N-(6-bromopyridazin-3-yl)-N,N-dimethylformimidamide

A mixture of 6-bromopyridazin-3-amine (1.74 g, 10 mmoles) and 1,1-dimethoxy-N,N-dimethylmethanamine (1.3 g, 11 mmoles) was stirred at 100°C for 3 hours. The mixture was cooled to room temperature and solidified on standing. The solid was filtered and dried in vacuo to give the title compound as a gray solid (1.85 g, 100%).

Step 2) 6-bromoimidazo[1,2-b]pyridazmo-3-carbonitrile

To a solution of NO-(6-bromopyridazin-3-yl)-N,N-dimethyl-formimidamide (1.23 g, 5.41 mmol) in acetonitrile (15 ml) was added bromoacetonitrile (1.13 ml, 16.25 mmoles). The mixture was stirred at 80°C overnight and then concentrated in vacuo. The residue was dissolved in a mixture of acetonitrile (15 ml) and DIPEA (6.0 ml, 35.60 mmoles). The resulting mixture was stirred at room temperature for 4 hours and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to give the title compound as a yellow solid (0.9 g, 75%). MS (ESI, pos. ion) m/z: 222.0 [M+H]+; 1 H-NMR (400 MHz, CDCl 3 ): h 8.22 (s, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.43 (d, J = 9.5 Hz, 1H).

Step 3) N-(5-(3-cyanoimidazo[1,2-b]pyridazin-6-yl)-2-methoxypyridin-3-yl)-4-fluorobenzenesulfonamide

To a mixture of 4-fluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (612 mg, 1.5 mmol), 6-bromoimidazo[1,2-b]pyridazine-3-carbonitrile (222 mg, 1.0 mmol), Pd(dppf)Cl2^CH2Cl2 (81.6 mg, 0, 1 mmol) and Na 2 CO 3 (424 mg, 4.0 mmol) were added 1,4-dioxane (25 ml) and water (5 ml). The mixture was stirred at 90°C under a N2 atmosphere for 5 hours, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/2) to give the title compound as a pale yellow solid (400 mg, 94%). MS (ESI, pos. ion) m/z: 425.0 [M+H]+; 1 H-NMR (400 MHz, DMSO-d6): h 3.80 (s, 3H), 7.41-7.48 (m, 2H), 7.89-7.97 (m, 2H), 8.16 (d, J = 9.7 Hz, 1H), 8.30 (d, J = 2.2 Hz, 1H), 8.46 (d, J = 9. 6 Hz, 1H), 8.61 (s , 1H), 8.72(d, J = 2.2 Hz, 1H). Example 7 N-(2-chloro-5-(3-ethylimidazo[1,2-b]pyridazm-6-yl)pyridm-3-yl)-4-fluorobenzenesulfonamide

Step 1) N-(2-chloro-5-(3-((trimethylsilyl)ethyl)imidazo[1,2-b]pyridazm-6-yl)-pyridin-3-yl)-4-fluorobenzenesulfonamide

To a mixture of (6-chloro-5-(4-fluorophenylsulfonamido)-pyridin-3-yl)boronic acid (521.0 mg, 1.58 mmol), 6-bromo-3-((trimethylsilyl) ethynyl)-imidazo[1,2-b]pyridazine (370.0 mg, 1.26 mmol), Pd(dppf)Cl2<H2Cl2 (71 mg, 0.087 mmol) and Na2CO3 (433 mg, 4.1 mmol) in 1,4-dioxane (20 ml) was added to water (4 ml). The mixture was stirred at 90°C under N2 atmosphere for 1 hour, then cooled to room temperature, and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give the title compound as white powder (110 mg, 11.5 %). MS (ESI, pos. ion) m/z: 500.0 [M+H]+.

Step 2) N-(2-chloro-5-(3-ethynimidazo[1,2-b]pyridazin-6-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide

To a solution of N-(2-chloro-5-(3-((trimethylsilyl)ethynyl)imidazo-[1,2-b]pyridazin-6-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (250.0 mg, 0.5 mmol) in THF (20 ml) was added 1 ml of TBAF (1 mmol, 1.0 M in THF). The resulting mixture was stirred at room temperature for 1 hour, then concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound as a pale yellow solid (80 mg, 37.6%). MS (ESI, pos. ion) m/z: 428.0 [M+H]+; 1 H-NMR (400 MHz, DMSO-d6): h 5.11 (s, 1H), 7.42-7.48 (t, J = 8.7 Hz, 2H), 7.87-7.91 (m, 2H), 8.00-8.03 (d, J =9.6 Hz, 1H), 8.19 (s, 1H), 8.35-8.42 (m, 2H), 8.95 (s , 1H), 10.65 (s, 1H). Example 8 N-(5-(3-ethynimidazo[1,2-b]pyridazin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

Step 1) 2,4-difluoro-N-(2-methoxy-5-(3-((trimethylsilyl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)pyridin-3-yl)benzenesulfonamide

To a mixture of 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl )benzenesulfonamide (349.0 mg, 0.82 mmol), 6-bromo-3-((trimethylsilyl)ethynyl)imidazo[1,2-b]pyridazine (200.0 mg, 0.64 mmol), Pd(dppf )Cl 2 ·CH 2 Cl 2 (55.6 mg, 0.064 mmol) and Na 2 CO 3 (338.8 mg, 3.196 mmol) in 1,4-dioxane (18 ml) was added to water (3 ml). The mixture was stirred at 90°C under N2 atmosphere for 1 hour, then cooled to room temperature, and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give the title compound as a white solid (160 mg, 46% ). MS (ESI, pos. ion) m/z: 514.0 [M+H]+.

Step 2) N-(5-(3-ethmilimidazo[1,2-b]pyridazm-6-yl)-2-methoxypyridm-3-yl)-2,4-difluorobenzenesulfonamide

To a solution of 2,4-difluoro-N-(2-methoxy-5-(3-((trimethylsilyl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)pyridin-3- yl)benzenesulfonamide (230.0 mg, 0.45 mmol) in THF (20 ml) was added 0.9 ml of TBAF (0.9 mmol, 1.0 M in THF). The solution was stirred at room temperature for 30 minutes, then concentrated in vacuo. The residue was purified by flash silica gel column chromatography (PE/EtOAc (v/v) = 1/3) to give the title compound as a white solid (100 mg, 51%). MS (ESI, pos. ion) m/z: 442.1 [M+H]+; 1 H-NMR (400 MHz, DMSO-d6): h 3.73 (s, 3H), 5.05 (s, 1H), 7.20-7.24 (t, J = 8.7 Hz, 1H), 7 .56-7.60 (t, J = 8. 6Hz, 1H), 7.78-7.84 (q, J =8.3 Hz, 1H), 7.947.96 (d, J = 9.6 Hz, 1H), 8.13 (s, 1H), 8.28-8.30 (m, 2H), 8.73-8.74 (d, J = 2.0 Hz, 1H). Example 9 2,4-difluoro-N-(5-(3-(3-hydroxyprop-1-yn-1-yl)imidazo[1,2-b]-pyridazin-6-yl)-2-methoxypyridin-3 -yl)benzenesulfonamide

To a suspension of 3-(6-bromoimidazo[1,2-b]pyridazin-3-yl)prop-2-yn-1-ol (1.69 g, 6.72 mmol) and Pd(PPh3 )2Cl2^CH2Cl2 (549 mg, 0.672 mmol) in DME (70 ml) was added a solution of Na2CO3 (1.78 g, 16.8 mmol) in water (20 ml), followed by the addition of a solution of 2, 4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-benzenesulfonamide (3.15 g, 7.39 mmoles) in DME (100 ml). The resulting mixture was stirred at 75°C under N 2 atmosphere for 4 hours, then cooled to room temperature, quenched with water (300 ml), and extracted with EtOAc (200 ml x 4). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to give the title compound as a yellow solid (1.3 g, 42%). MS (ESI, pos. ion) m/z: 472.0 [M+H]+; 1 H-NMR (400 MHz, DMSO-d6): h 10.43 (s, 1H), 8.74-8.73 (d, J = 2.2 Hz, 1H), 8.30-8.27 (m, 2H), 8.06 (s, 1H), 7.92-7.90 (d, J = 9.5 Hz, 1H), 7.83-7.77 (m, 1H), 7.60-7 .54 (m, 1H), 7.24-7.19 (m, 1H), 5.53-5.51 (m, 1H), 4.50-4.48 (d, J = 5.6 Hz , 1H), 3.72 (s, 3H). Example 10 2,4-difluoro-N-(5-(3-(3-hydroxybut-1-yn-1-yl)imidazo[1,2-b]-pyridazm-6-yl)-2-methoxypyridm-3 -yl)benzenesulfonamide

[00212] To a suspension of 4-(6-bromoimidazo[1,2-b]pyridazin-3-yl)but-3-yn-2-ol (400 mg, 1.50 mmol), PdCdppfCVCHiCli (123 mg, 0.15 mmol) and 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridine-3-yl )benzenesulfonamide (705mg, 1.65mmol) in DME (41ml) was added a solution of Na 2 CO 3 (398mg, 3.76mmol) in water (6ml). The mixture was stirred at 75°C under N 2 atmosphere for 3.5 hours, then cooled to room temperature, quenched with H 2 O (200 ml), and extracted with EtOAc (200 ml x 4). The combined organic layers were concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give the title compound as a yellow solid (300 mg, 41 %). MS (ESI, pos. ion) m/z: 486.0 [M+H]+; 1 H-NMR (400 MHz, DMSO-d6): h 10.41 (s, 1H), 8.75-8.74 (d, J = 2.2 Hz, 1H), 8.36-8.35 (d, J = 2.2 Hz, 1H), 8.28-8.26 (d, J = 9.5 Hz, 1H), 8.06 (s, 1H), 7.93-7.91 (d, J = 9.5Hz, 1H), 7.82-7.68 (m, 1H), 7.59-7.54 (m, 1H), 7.237.18 (m, 1H), 5.65-5, 64 (d, J = 5.4 Hz, 1H), 4.80-4.74 (m, 1H), 3.72 (s, 3H), 1.50-1.49 (d, J = 6. 6Hz, 3H). Example 11 2,4-difluoro-N-(5-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)imidazo[1,2-b]pyridazm-6-yl)-2- methoxypyridm-3-yl)benzenesulfonamide

Step 1) 2,4-difluoro-N-(5-(imidazo[1,2-b]pyridazm-6-yl)-2-methoxypyridm-3-yl)benzenesulfonamide

To a mixture of 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl )benzenesulfonamide (2.13 g, 5.0 mmoles), 6-bromoimidazo[1,2-b]pyridazine (1 g, 0.79 mmol), Pd(dppf)ClrCH2Cl2 (408 mg, 0.5 mmol) and Na2CO3 (1.32 g, 12.5 mmol) was added DME (120 ml) and water (30 ml). The mixture was stirred at 70°C under N 2 atmosphere for 4 hours, then cooled to room temperature, quenched with H 2 O (500 ml), and then extracted with EtOAc (500 ml x 3). The combined organic phases were concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v) = 200/3) to give the title compound as a light brown solid (1.28 g, 61.4%). MS (ESI, pos. ion) m/z: 418.0 [M+H]+.

Step 2) N-(5-(3-bromoimidazo[1,2-b]pyridazm-6-yl)-2-methoxypyridm-3-yl)-2,4-difluorobenzenesulfonamide

To a solution of 2,4-difluoro-N-(5-(imidazo[1,2-b]pyridazin-6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide (1.28 g, 3 .07 mmoles) in DMF (30 ml) was added NBS (545.8 mg, 3.07 mmoles) in portions. The reaction was stirred at -20°C for 12 hours and then quenched with H2O (100 ml). The mixture was continued to stir overnight and then filtered. The solid was collected and purified by preparative HPLC to give the title compound as a pale yellow solid (320 mg, 21 %). MS (ESI, pos. ion) m/z: 496.1 [M+H]+.

Step 3) 2,4-difluoro-N-(5-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)imidazo[1,2-b]-pyridazm-6-yl)- 2-methoxypyridm-3-yl)benzenesulfonamide

To a suspension of N-(5-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (100mg, 0, 21 mmol), Pd(PPh3)2Cl2 (15 mg, 0.02 mmol), CuI (4 mg, 0.02 mmol) and DIPEA (67 mg, 0.52 mmol) in DMF (2 ml) was added 2- methylbut-3-yn-2-ol (53 mg, 0.63 mmol). The mixture was stirred at room temperature under N2 atmosphere for 6 hours and then concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound as a yellow solid (36 mg, 35%). MS (ESI, pos. ion) m/z: 500.5 [M+H]+; 1 H-NMR (400 MHz, CDCl 3 ): h 8.59-8.58 (d, J = 2.2 Hz, 1H), 8.46-8.45 (d, J = 2.2 Hz, 1H), 8 .00-7.94 (m, 3H), 7.47 (s, 1H), 6.96-6.90 (m, 2H), 4.01 (s, 3H), 3.18(s, 1H) ), 2.97 (s, 1H), 1.57 (s, 6H). Example 12 4-fluoro-N-(5-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)-[1,2,4]triazolo[4,3-b]pyridazm-6 -yl)-2-methoxypyridin-3-yl)benzenesulfonamide

Step 1) 6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ol

A mixture of 3,6-dichloropyridazine (4.5 g, 30.4 mmol), hydrazinecarboxamide hydrochloride (6.7 g, 60.8 mmol) and three drops of conc. in EtOH (30 ml) was sealed in a microwave flask and heated in a microwave at 120 oC for 1 hour. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was washed with H 2 O (15 ml) and Et 2 O (20 ml), then filtered, and the filter cake was dried in vacuo to give the title compound as a yellow solid (1.8 g, 32%). MS (ESI, pos. ion) m/z: 171.0 [M+H]+; 1 H-NMR (400 MHz, CDCl 3 ): h 7.89 (d, J = 9.8 Hz, 1H), 7.20 (d, J = 9.8 Hz, 1H).

Step 2) 3,6-dichloro-[1,2,4]triazolo[4,3-b]pyridazine

[00217] A mixture of 6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ol (1.8 g, 10.6 mmoles) and PCl5 (0.4 g, 2 mmoles) in POCl3 (20 ml) was stirred at 120°C for 12 hours and concentrated in vacuo. The residue was quenched with ice water (50 ml) at 0°C. The resulting mixture was extracted with EtOAc (50 ml x 2). The combined organic phases were washed with brine (100 ml), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 3/1) to give the title compound as a pale yellow solid (0.5 g, 20%). MS (ESI, pos. ion) m/z: 189.0 [M+H]+; 1 H-NMR (400 MHz, CDCl 3 ): h 8.08 (d, J = 9.7 Hz, 1H), 8.73 (d, J = 9.7 Hz, 1H).

Step 3) N-(5-(3-chloro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2-methoxypyridin-3-yl)-4-fluorobenzenesulfonamide

[00218] To a suspension of 3,6-dichloro-[1,2,4]triazolo[4,3-b]pyridazine (0.5 g, 1.8 mmol), 4-fluoro-N-(2- methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (0.8 g, 2.2 mmol) and Pd(dppf) Cl2^CH2Cl2 (0.15g, 0.18mmol) in DME (20ml) was added a solution of Cs2CO3 (1.2g, 3.6mmol) in H2O (2ml). The resulting mixture was stirred at 70°C under N 2 atmosphere for 12 hours and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/2) to give the title compound as a pale yellow solid (0.5 g, 64%). MS (ESI, pos. ion) m/z: 435.0 [M+H]+; 1 H-NMR (400 MHz, CDCl 3 ): h 10.20 (s, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.46 (d, J = 9.8 Hz, 1H), 8.27 (d, J = 2.2 Hz, 1H), 8.04 (d, J = 9.8 Hz, 1H), 7.90-7.87 (m, 2H), 7.42-7 .38 (m, 2H), 3.79 (s, 3H).

Step 4) 4-fluoro-N-(5-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)-[1,2,4]triazolo[4,3-b]pyridazm- 6-yl)-2-methoxypyridm-3-yl)benzenesulfonamide

[00219] A mixture of N-(5-(3-chloro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2-methoxypyridin-3-yl)-4-fluorobenzenesulfonamide (0.4 g, 0.96 mmol), 2-methylbut-3-yn-2-ol (0.16 g, 0.2 mmol), Pd2(dba)3 (0.04 g, 0.04 mmol) ), CuI (0.04 g, 0.16 mmol), i-Pr2NH (0.29 g, 2.88 mmol) and X-Phos (0.09 g, 0.16 mmol) in DMF (20 ml) was stirred at 100°C under N2 atmosphere for 36 hours. The mixture was then concentrated in vacuo and the residue was purified by a silica gel column chromatography (DCM/MeOH = 50/1) to give the title compound as a yellow solid (0.3 g, 68%). MS (ESI, pos. ion) m/z: 483.0 [M+H]+; 1 H-NMR (400 MHz, CDCl 3 ): h 10.20 (s, 1H), 8.75 (d, J = 2.2 Hz, 1H), 8.51 (d, J = 9.8 Hz, 1H), 8.44 (d, J = 2.2 Hz, 1H), 8.06 (d, J = 9.8 Hz, 1H), 7.87-7.84 (m, 2H), 7.43-7 .38 (m, 2H), 3.75 (s, 3H), 1.60 (s, 6H). Example 13 2,4-difluoro-N-(2-methoxy-5-(3-(prop-1-yn-1-yl)imidazo[1,2-b]-pyridazin-6-yl)pyridin-3- il)benzenesulfonamide

Step 1) 6-chloro-3-(prop-1-in-1-yl)imidazo[1,2-b]pyridazine

[00220] To a suspension of 6-chloro-3-iodoimidazo[1,2-b]pyridazine (3 g, 10.7 mmoles), Pd(PPh3)2Cl2 (750 mg, 1.07 mmol), CuI (200 mg, 1.07 mmol), and diisopropylethylamine (7.5 ml, 53.5 mmol) in 107 ml of DMF was added Propine (about 3% in Heptane, 60 ml, 21.4 mmol). The mixture was stirred at room temperature under N 2 atmosphere for 4 hours, then H 2 O (300 ml) was added and the resulting mixture was extracted with EtOAc (300 ml x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (pure DCM) to furnish the title compound as a yellow solid (560 mg, 27%). MS (ESI, pos. ion) m/z: 192.3 [M+H]+.

Step 2) 2,4-difluoro-N-(2-methoxy-5-(3-(prop-1-yn-1-yl)imidazo[1,2-b]-pyridazin-6-yl)pyridin-3 -yl)benzenesulfonamide

[00221] To a suspension of 6-chloro-3-(prop-1-in-1-yl)imidazo[1,2-b]-pyridazine (560 mg, 2.9 mmoles), 2,4-difluoro- N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (1.5 g, 3.5 mmoles) and Pd(dppf)Cl2<H2Cl2 (237 mg, 0.29 mmol) in 1,4-dioxane/H2O (30 ml/6 ml) was added Na2CO3 (774 mg, 7.3 mmol). The resulting mixture was purged with N2 three times and stirred at 90°C sealed under N2 atmosphere for 5 hours, then cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 100/1) to give the title compound as a pale yellow solid (700 mg, 53%). MS (ESI, pos. ion) m/z: 455.9 [M+H]+; Purity: 97.6%; 1 H-NMR (600 MHz, DMSO-d6): h 10.46 (s, 1H), 8.73 (d, J = 2.0 Hz, 1H), 8.31 (d, J = 2.2 Hz, 1H ), 8.26 (d, J = 9.5 Hz, 1H), 8.01 (s, 1H), 7.89 (d, J = 9.5 Hz, 1H), 7.79 (d, J = 6.3 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.22 (td, J = 8.5, 2.2 Hz, 1H), 3.72 (s , 3H), 2.25 (s, 3H). Example 14 N-(5-(3-cyanoimidazo[1,2-b]pyridazin-6-yl)-2-methoxypyridin-3-yl)cyclopropanesulfonamide

Step 1) 5-bromo-2-methoxy-3-nitropyridine

To a cooled solvent of MeOH (50.0 ml) was added Na (2.90 g, 126.4 mmoles) in portions, then the mixture was warmed to room temperature and stirred until the Na was all dissolved. , then the solution was added to a suspension of 5-bromo-2-chloro-3-nitropyridine (10.0 g, 42.12 mmoles, Shanghai long sheng hua gong, China) in MeOH (100 ml) at 0°C. The reaction mixture was stirred at 0°C for 1 hour, then warmed to room temperature and stirred for a further 16 hours, then concentrated to 80 ml and quenched with water (100 ml). The precipitate was filtered, washed with water (50 ml x 2) and dried under infrared light to give the title compound as a pale yellow solid (9.62 g, 98%). MS (ESI, pos. ion) m/z: 233.0 [M+H]+.

Step 2) 5-bromo-2-methoxypyridin-3-amine

[00223] To a suspension of 5-bromo-2-methoxy-3-nitropyridine (9.62 g, 41.3 mmoles) in ethanol (100 ml) and water (10 ml) was added Iron powder (9.25 g, 165.2 mmoles, Tianjin guangfukeji) and NH 4 Cl (8.83 g, 165.2 mmoles). The mixture was heated to reflux and stirred for a further 15 hours, then cooled to room temperature, and concentrated in vacuo. The residue was dissolved in 250 ml of EtOAc and the resulting solution was washed with saturated aqueous sodium bicarbonate solution (100 ml), water (100 ml x 2) and brine (150 ml), dried over anhydrous Na2SO4, and concentrated to vacuum to give the title compound as a yellow solid (8.16 g, 97%). MS (ESI, pos. ion) m/z: 202.8 [M+H]+.

Step 3) N-(5-bromo-2-methoxypyridm-3-yl)cyclopropanesulfonamide

To a suspension of 5-bromo-2-methoxypyridin-3-amine (200mg, 0.99mmol) in pyridine (10ml) was added cyclopropanesulfonyl chloride (346mg, 2.46mmol) slowly . The reaction was stirred at room temperature for 18 hours, then heated to 60°C and stirred for 5 hours. The mixture was cooled to room temperature, then acidified to pH = 2 with 1 M HCl (aq.), and the resulting mixture was extracted with DCM (15 ml x 3). The combined organic layers were washed with water (20 ml x 2) and brine (20 ml), dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc(v/v) = 5/1) to give the title compound as a yellow solid (191 mg, 63%). MS (ESI, pos. ion) m/z: 306.9 [M+H]+; 1 H-NMR (600 MHz, CDCl3): h 7.96 (d, J = 2.22 Hz, 1H), 7.92 (d, J = 2.22 Hz, 1H), 6.70 (brs, 1H), 4.00 (s, 3H), 2.56-2.47 (m, 1H), 1.26-1.20 (m, 2H), 1.040.97 (m, 2H).

Step 4) N-(2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)cyclopropanesulfonamide

A solution of N-(5-bromo-2-methoxypyridin-3-yl)cyclopropanesulfonamide (50 mg, 0.163 mmol), 4,4,4O,4O,5,5,5O,5O-octamethyl- 2,2O-bi(1,3,2-dioxaborolane) (166mg, 0.652mmol, Beijing datianfengtuo) and KOAc (64mg, 0.652mmol) in 1,4-dioxane (10ml) was degassed and charged with N 2 per 3 times, then 1\](clppf)Cl:<I bCb (27 mg, 0.0326 mmol, matthey) was added. The mixture was heated to 80°C and stirred for a further 2.5 hours, then cooled to room temperature, concentrated in vacuo and the residue dissolved in DCM (20 ml). The resulting mixture was filtered through a pad of CELITE®. The filtrate was washed with water (15 ml x 3) and brine (15 ml), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (1E/EtOAc (v/v) = 5/2) to give the title compound as a white solid (50 mg, 86%). MS (ESI, pos. ion) m/z: 355.1 [M+I]+; 1 I NMR (600 MIz, CDCl3): h 8.30 (d, J = 1.65 Iz, 1I), 8.08 (d, J = 1.65 Iz, 1I), 6.64 (brs, 1I), 4.03 (s, 3I), 2.60-2.40 (m, 1I), 1.33 (s, 12I), 1.22-1.15 (m, 2I), 0.99-0, 93 (m, 2I).

Step 5) N-(5-(3-cyanoimidazo[1,2-b]pyridazin-6-yl)-2-methoxypyridin-3-yl)cyclopropanesulfonamide

To a solution of 6-bromoimidazo[1,2-b]pyridazine-3-carbonitrile (50 mg, 0.23 mmol) in 1,4-dioxane (10 ml) was added N-(2-methoxy- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)cyclopropanesulfonamide (88mg, 0.25mmol), Na2CO3 (48mg, 0 .46 mmol), H 2 O (2 ml) and el 1 ](dppf)Cl 2 Cl 2 Cl hCl: (37 mg, 0.046 mmol). The mixture was heated to 80°C and stirred for a further 1 hour, then cooled to room temperature, and concentrated in vacuo. The residue was extracted with DCM (10 ml x 3). The combined organic phases were dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (DCM/MeOH (v/v) = 200/1) to give the title compound as a pale pink solid (60 mg, 72%). MS (ESI, pos. ion) m/z: 371.0 [M+H]+; 1 H-NMR (600 MHz, CDCl3): h 8.60 (d, J = 2.4 Hz, 1H), 8.40 (d, J = 2.1 Hz, 1H), 8.27 (s, 1H), 8.16 (d, J = 9.6 Hz, 1H), 7.70 (d, J = 9.9 Hz, 1H), 6.85 (brs, 1H), 4.14 (s, 3H), 2.63-2.57 (m, 1H), 1.36-1.25 (s, 2H), 1.14-1.09 (m, 2H). Example 15 2,4-difluoro-N-(5-(3-(3-hydroxyprop-1-yn-1-yl)imidazo[1,2-um]pyridin-6-yl)-2-methoxypyridin-3- il)benzenesulfonamide

Step 1) 6-bromoimidazo[1,2-a]pyridine

[00227] To a solution of 5-bromopyridin-2-amine (10.0 g, 57.7 mmoles) in EtOH/H2O (100 ml/20 ml) was added 2-chloroacetaldehyde (10.5 g, 86.7 mmoles) slowly. The mixture was heated to 80°C and stirred for a further 15 hours, then cooled to room temperature and concentrated in vacuo. A saturated aqueous solution of NaHCO3 (200 ml) was added to the residue. The resulting mixture was extracted with DCM (200 ml x 3). The combined organic phases were concentrated in vacuo to give the title compound as a brown solid (11.3 g, 100%). MS (ESI, pos. ion) m/z: 197.1 [M+H]+.

Step 2) 2,4-difluoro-N-(5-(imidazo[1,2-a]pyridm-6-yl)-2-methoxypyridm-3-yl)benzenesulfonamide

A mixture of 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl) benzenesulfonamide (23.8 g, 55.2 mmoles), 6-bromoimidazo[1,2-b]pyridazine (10.0 g, 50.8 mmol), Pd(dppf)Cl2^CH2Cl2 (4.15g, 5, 1 mmol) and N 2 CO 3 (13.2 g, 127.5 mmol) in DME (250 ml) and water (50 ml) was degassed and charged with N 2 3 times. The mixture was heated to 70°C and stirred for 6 hours, then cooled to room temperature, filtered through a pad of CELITE®, and the filtrate concentrated in vacuo. The residue was purified by a silica column chromatography (pure EtOAc) to give the title compound as a white solid (15.1 g, 70.4%). MS (ESI, pos. ion) m/z: 417.0 [M+H]+.

Step 3) 2,4-difluoro-N-(5-(3-iodoimidazo[1,2-um]pyridm-6-yl)-2-methoxy-pyridm-3-yl)benzenesulfonamide

[00229] To a solution of 2,4-difluoro-N-(5-(imidazo[1,2-a]pyridin-6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide (12.7 g, 30 .5 mmoles) in DMF (130 ml) was added NIS (17.2 g, 30.5 mmoles) slowly. The mixture was stirred at 45°C for 6 hours, then H 2 O (150 ml) was added and stirred at room temperature for a further 1 hour. Filtered and the filter cake washed with EtOAc (20 ml) to give the title compound as a white solid (15.4 g, 90%). MS (ESI, pos. ion) m/z: 543.0 [M+H]+.

Step 4) 2,4-difluoro-N-(5-(3-(3-hydroxyprop-1-m-1-yl)imidazo[1,2-a]pyridm-6-yl)-2-methoxypyridm-3 -yl)benzenesulfonamide

[00230] To a suspension of 2,4-difluoro-N-(5-(3-iodoimidazo[1,2-a]pyridin-6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide (15.0 g) , 27.6 mmoles), Pd(PPh3)2Cl2 (2.0 g, 2.9 mmoles), CuI (0.55 g, 2.8 mmoles) and Et3N (14.0 g, 137.5 mmoles) in 70 ml of DMF was added prop-2-yn-1-ol (5.6 g, 99.6 mmol). The mixture was stirred at 50 °C under N2 atmosphere for 6 hours, then cooled to room temperature, filtered and the filtrate was concentrated in vacuo. H2O (100 ml) was added to the residue and the resulting mixture was filtered. The filter cake was purified by a silica gel column chromatography (DCM/MeOH (v/v) = 50/1) to give the crude product, then the crude product was washed with EtOAc/MeOH (20 ml/10) ml) to give the title compound as a yellow solid (6.7 g, 50.4%). MS (ESI, pos. ion) m/z: 471.0[M+H]+; 1 H-NMR (600 MHz, DMSO-d6): h 10.36 (s, 1H), 8.62 (s, 1H), 8.41 (d, J = 2.2 Hz, 1H), 7.98 (d , J = 2.3 Hz, 1H), 7.83-7.71 (m, 1H), 7.87-7.50 (m, 3H), 7.687.50 (m, 1H), 7.22 ( td, J = 8.5, 2.2 Hz, 1H), 5.48 (t, J = 5.9 Hz, 1H), 4.50 (d, J = 5.8 Hz, 2H), 3, 66 (s, 3H). Example 16 2,4-difluoro-N-(5-(3-(3-hydroxybut-1-yn-1-yl)imidazo[1,2-a]-pyridin-6-yl)-2-methoxypyridm-3 -yl)benzenesulfonamide

[00231] To a suspension of 2,4-difluoro-N-(5-(3-iodoimidazo[1,2-a]-pyridin-6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide (1.5 g, 2.7 mmol), Pd(PPh3)2Cl2 (0.2 g, 0.3 mmol), CuI (0.06 g, 0.3 mmol) and Et3N (1.4 g, 13.5 mmol) in 7 ml of DMF was added but-3-yn-2-ol (0.7 g, 9.9 mmoles). The mixture was stirred at 50 °C under N2 atmosphere for 6 hours, then cooled to room temperature, filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v) = 50/1) to give the title compound as a yellow solid (0.5 g, 40.1%). MS (ESI, pos. ion) m/z: 485.1 [M+H]+; 1 H-NMR (600 MHz, CDCl 3 ): h 8.39 (s, 1H), 8.10 (d, J = 1.9 Hz, 1H), 7.97 (t, J = 13.6 Hz, 1H), 7.90 (dd, J = 14.4, 8.3 Hz, 1H), 7.84 (s, 1H), 7.47 (d, J = 3.5 Hz, 1H), 7.37 (s , 1H), 6.97 (dt, J = 15.8, 8.2 Hz, 2H), 4.93 (q, J = 6.6 Hz, 1H), 4.03 (s, 3H), 3 .49 (s, 1H), 1.65 (d, J = 6.6 Hz, 3H). Example 17 2,4-difluoro-N-(5-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)imidazo[1,2-a]pyridm-6-yl)-2- methoxypyridm-3-yl)benzenesulfonamide

To a suspension of 2,4-difluoro-N-(5-(3-iodoimidazo[1,2-a]pyridin-6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide (1.5 g , 2.7mmol), Pd(PPh3)2Cl2 (0.2g, 0.3mmol), CuI (0.06g, 0.3mmol) and Et3N (1.4g, 13.5mmol) in 7 ml of DMF was added 2-methylbut-3-yn-2-ol (0.8 g, 9.9 mmoles). The mixture was stirred at 50 °C under N2 atmosphere for 6 hours, then cooled to room temperature, filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v) = 50/1) to give the title compound as a yellow solid (0.6 g, 40%). MS (ESI, pos. ion) m/z: 499.1 [M+H]+; 1 H-NMR (600 MHz, DMSO-d6): h 10.38 (s, 1H), 8.52 (d, J = 0.7 Hz, 1H), 8.41 (d, J = 2.3 Hz, 1H ), 7.97 (d, J = 2.3 Hz, 1H), 7.90 (s, 1H), 7.81-7.74 (m, 2H), 7.67 (dd, J = 9. 3, 1.8 Hz, 1H), 7.61-7.56 (m, 1H), 7.22 (td, J = 8.5, 2.3 Hz, 1H), 5.71 (s, 1H ), 3.68 (s, 3H), 1.57 (s, 6H). Example 18 2,4-difluoro-N-(2-methoxy-5-(3-(prop-1-yn-1-yl)imidazo[1,2-a]-pyridin-6-yl)pyridin-3- il)benzenesulfonamide

To a mixture of 2,4-difluoro-N-(5-(3-iodoimidazo[1,2-a]-pyridin-6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide (1.50 g, 2.76 mmol), Pd(PPh3)2Cl2 (0.189 g, 0.27 mmol) and CuI (52 mg, 0.27 mmol) in 20 ml DMF was added diisopropylethylamine (1.78 g, 13.8 mmoles). The mixture was degassed and charged with nitrogen three times, then propine (0.44 g, 11.04 mmoles) was added via syringe. The resulting mixture was stirred at 45°C under N 2 atmosphere for 10 hours, and concentrated in vacuo. H2O (40 ml) was added and the resulting mixture was stirred at room temperature for 1 hour, filtered and the filter cake was purified by scintillating silica gel column chromatography (DCM/MeOH (v/v) = 300/ 1) to give the title compound as a yellow solid (220 mg, 17.52%). MS (ESI, pos. ion) m/z: 454.9 [M+H]+; 1 H-NMR (600 MHz, DMSO-d6): h 10.46 (s, 1H), 9.18 (d, J = 7.3 Hz, 1H), 8.86 (s, 1H), 8.41 (s , 1H), 8.34 (s, 1H), 7.78 (dd, J = 14.6, 8.0 Hz, 1H), 7.72 (d, J = 7.3 Hz, 1H), 7 .58 (t, J = 9.1 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 3.71 (s, 3H), 2.14 (s, 3H). Example 19 N-(5-(3-cyanoimidazo[1,2-a]pyridin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

Step 1) N-(5-chloropyridin-2-yl)-N,N-dimethylformimidamide

A mixture of 5-chloropyridin-2-amine (1.29 g, 10 mmoles) and Dimethoxy-N,N-dimethylmethanamine (1.31 g, 11 mmoles) was stirred at 100°C for 3 hours, then cooled to room temperature, and a yellow solid formed in the homogeneous solution. Filtered, and the filter cake dried in vacuo to give the title compound as a yellow solid (1.85 g, 100%), the crude product was used in the next step without further purification. MS (ESI, pos. ion) m/z: 184.0 [M+H]+.

Step 2) 6-chloroimidazo[1,2-a]pyridine-3-carbonitrile

To a solution of NO-(5-chloropyridin-2-yl)-N,N-dimethyl-formimidamide (1.83 g, 10 mmoles) in acetonitrile (30 ml) was added bromoacetonitrile (3.6 g, 30 mmoles). The reaction was stirred at 80 °C overnight, then cooled to room temperature, and diisopropylethylamine (12.0 ml, 70 mmol) was added. The resulting mixture was stirred at room temperature for 4 hours and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (pure DCM) to give the title compound as a yellow solid (0.9 g, 51%). MS (ESI, pos. ion) m/z: 178.0 [M+H]+.

Step 3) N-(5-(3-cyanoimidazo[1,2-a]pyridin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[00236] A mixture of 6-chloroimidazo[1,2-a]pyridine-3-carbonitrile (900 g, 5.07 mmoles), 2,4-difluoro-N-(2-methoxy-5-(4,4) ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (3.24 g, 7.06 mmoles), PdCdppfCirCHiCh (416 mg, 0.51 mmol) and \ a2CO3 (2.15 g, 20.28 mmoles) was degassed and charged with N2 3 times, followed by the addition of 1,4-dioxane (125 ml) and water (25 ml). The mixture was degassed and charged with N2 3 times, then heated to 90°C and stirred for a further 6 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =2/1) to give the title compound as a light brown solid (280 mg, 12%). MS (ESI, pos. ion) m/z: 442.1 [M+H]+; 1 H-NMR (400 MHz, CDCl 3 ): h 8.39 (s, 1H), 8.24 (s, 1H), 8.11 (s, 1H), 7.95 (q, J = 8.7 Hz, 3H ), 7.63 (d, J = 9.0 Hz, 1H), 7.38 (s, 1H), 7.04 (t, J = 8.1 Hz, 1H), 6.99 (t, J = 9.2 Hz, 1H), 4.02 (s, 3H). Example 20 N-(5-(3-(3-hydroxyprop-1-yn-1-yl)imidazo[1,2-a]pyridin-6-yl)-2-methoxypyridin-3-yl)cyclopropanesulfonamide

Step 1) N-(5-(imidazo[1,2-a]pyridin-6-yl)-2-methoxypyridin-3-yl)cyclopropanesulfonamide

To a solution of 6-bromoimidazo[1,2-a]pyridine (318 mg, 1.61 mmol) in 1,4-dioxane (15 ml) was added N-(2-methoxy-5- (4') ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)cyclopropanesulfonamide (600mg, 1.69mmol), KOAc (316mg, 3.22mmol), H2O (3 ml) and Pd(dppf)Cl 2 ·CH 2 Cl 2 (131 mg, 0.161 mmol). The reaction was heated to 85°C and stirred for a further 5 hours under a N2 atmosphere, then cooled to room temperature and concentrated in vacuo. The residue was dissolved in DCM (200 ml) and the resulting mixture was filtered through a CELITE®. The filtrate was washed with H2O (100 ml) and brine (100 ml). The combined aqueous layers were extracted with DCM (50 ml x 3). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (DCM/MeOH (v/v) = 65/1) to give the title compound as a yellowish solid (342 mg, 62%). MS (ESI, pos. ion) m/z: 345.0 [M+H]+; 1 H-NMR (600 MHz, DMSO-d6): h 9.42 (s, 1H), 8.91 (s, 1H), 8.35 (d, J = 2.1 Hz, 1H), 7.99 (s , 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.68-7.61 (m, 2H), 7.54 (dd, J = 1.8, 9.6 Hz, 1H), 3.98 (s, 3H), 2.82-2.74 (m, 1H), 1.00-0.89 (m, 4H).

Step 2) N-(5-(3-iodoimidazo[1,2-a]pyridm-6-yl)-2-methoxypyridm-3-yl)cyclopropanesulfonamide

[00238] To a solution of N-(5-(imidazo[1,2-a]pyridin-6-yl)-2-methoxy-pyridin-3-yl)cyclopropanesulfonamide (292 mg, 0.85 mmol) in acetonitrile (20 ml) was added NIS (210 mg, 0.933 mmol) at 0 °C. The mixture was heated to 84°C and stirred for a further 1 hour, then cooled to room temperature, and filtered. The filter cake was vacuum dried to give the crude product, and the filtrate was concentrated in vacuo. The residue was dissolved in DCM (20 ml). The resulting mixture was washed with Na 2 S 2 O 3 (aq., 10%, 10 ml), Na 2 CO 3 (aq., 1 M, 10 ml), H 2 O (10 ml) and brine (10 ml), and extracted with DCM (10 ml x 3). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue together with the above crude product was purified by a flash silica gel column chromatography (DCM/MeOH (v/v) = 95/1) to give the title compound as a white solid (293 mg, 73% ). MS (ESI, pos. ion) m/z: 471.0 [M+H]+; 1 H-NMR (600 MHz, DMSO-d6): h 9.44 (s, 1H), 8.39 (d, J = 2.4 Hz, 2H), 7.97 (d, J = 2.4 Hz, 1H ), 7.77 (s, 1H), 7.73 (d, J = 9.3 Hz, 1H), 7.61 (dd, J = 1.8, 9.3 Hz, 1H), 3.99 (s, 3H), 2.88-2.72 (m, 1H), 0.98-0.92 (m, 4H).

Step 3) N-(5-(3-(3-hydroxyprop-1-yn-1-yl)imidazo[1,2-a]pyridin-6-yl)-2-methoxypyridm-3-yl)cyclopropanesulfonamide

[00239] To a suspension of N-(5-(3-iodoimidazo[1,2-a]pyridin-6-yl)-2-methoxypyridin-3-yl)cyclopropanesulfonamide (85mg, 0.18mmol), CuI (20.6 mg, 0.108 mmol) and Pd(PPh3)4 (41.6 mg, 0.036 mmol) in DMF (3 ml) were added triethylamine (0.05 ml, 0.36 mmol) and prop-2-yn -1-ol (0.03 ml, 0.54 mmol). The mixture was degassed and charged with argon 3 times, then stirred at room temperature for 2.5 hours, diluted with EtOAc (10 ml), and filtered through a CELITE®. The filtrate was washed with aqueous sodium bicarbonate solution (20 ml) and H2O (20 ml). The combined aqueous layers were extracted with DCM (10 ml x 3). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (DCM/MeOH (v/v) = 50/1) to give the title compound as a yellow solid (50 mg, 69%). MS (ESI, pos. ion) m/z: 399.0 [M+H]+; 1 H-NMR (600 MHz, DMSO-d6): h 9.45 (s, 1H), 8.66 (brs, 1H), 8.40 (d, J = 2.19 Hz, 1H), 7.95 (d , J = 2.16 Hz, 1H), 7.80 (brs, 1H), 7.68 (brs, 1H), 5.46 (t, J = 6.06 Hz, 1H), 4.48 (d , J = 4.86 Hz, 2H), 3.99 (s, 3H), 2.83-2.74 (m, 1H), 0.97-0.91 (m, 4H). Example 21 N-(5-(3-cyanoimidazo[1,2-a]pyridin-6-yl)-2-methoxypyridin-3-yl)methanesulfonamide

Step 1) N-(5-bromo-2-methoxypyridin-3-yl)methanesulfonamide

To a suspension of 5-bromo-2-methoxypyridin-3-amine (8.16 g, 40.2 mmoles) in DCM (100 ml) was added pyridine (9.71 ml, 120.6 mmoles), followed by the addition of a solution of methanesulfonyl chloride (7.78 ml, 100.5 mmoles) in DCM (20 ml) dropwise at room temperature. The reaction was stirred at room temperature for 24 hours and quenched with aqueous HCl solution (1 M, 30 ml). The resulting mixture was extracted with DCM (15 ml x 2). The combined organic phases were washed with water (50 ml x 2) and concentrated in vacuo. The residue was dissolved in methanol (50 ml), then aqueous NaOH solution (2M, 50 ml) was added and the mixture stirred at room temperature for 30 minutes. Methanol was removed under reduced pressure and the aqueous phase was extracted with DCM (30 ml x 4). The aqueous phase was then acidified to pH = 2 with aqueous HCl solution (2M). The resulting precipitate was collected by filtration to give the title compound as a white solid (6.40 g, 57%). MS (ESI, pos. ion) m/z: 280.8 [M+H]+.

Step 2) N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide

[00241] A suspension of N-(5-bromo-2-methoxypyridin-3-yl)methanesulfonamide (3.35 g, 11.9 mmoles) and 4,4,40,40,5,5,50, 5O-octamethyl-2,2O-bi(1,3,2-dioxaborolane) (4.24 g, 16.7 mmol, Beijing datianfengtuo) in toluene (100 ml) was degassed and charged with N2 3 times, then Pd (dba)3 (616mg, 0.595mmol, Matthey) and PPh3 (243mg, 0.892mmol) were added. The mixture was heated to 45°C and stirred for 45 minutes, then KOAc (3.74 g, 23.8 mmol) was added. The resulting mixture was heated to reflux and stirred for a further 3 hours, then cooled to room temperature, diluted with EtOAc (100 ml), and filtered through a CELITE®. The filtrate was washed with water (70 ml x 3) and brine (100 ml), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to give the title compound as a white solid (2.90 g, 74%). MS (ESI, pos. ion) m/z: 328.9 [M+H]+; 1 H-NMR (600 MHz, CDCl3): h 8.32 (d, J = 1.4 Hz, 1H), 8.06 (d, J = 1.3 Hz, 1H), 6.66 (brs, 1H), 4.05 (s, 3H), 3.02 (s, 3H), 1.33 (s, 12H).

Step 3) N-(5-(3-cyanoimidazo[1,2-a]pyridin-6-yl)-2-methoxypyridin-3-yl)-methanesulfonamide

A suspension of 6-bromoimidazo[1,2-a]pyridine-3-carbonitrile (50 mg, 0.22 mmol) in 1,4-dioxane/water (5 ml/1 ml) was degassed and charged with N2 three times, then Pd(dppf)Cl2 (37 mg, 0.045 mmol), N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3-yl)methanesulfonamide (111 mg, 0.338 mmol) and Na 2 CO 3 (48 mg, 0.450 mmol) were added to the mixture successively. The mixture was heated to reflux and stirred for a further 65 minutes, then cooled to room temperature, and concentrated in vacuo. The residue was dissolved in DCM (20 ml) and water (20 ml). The resulting mixture was separated, and the aqueous layer was extracted with DCM (10 ml x 2). The combined organic phases were washed with water (25 ml) and brine (25 ml), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v) = 100/1) to give the title compound as a pale pink solid (35 mg, 46%). MS (ESI, pos. ion) m/z: 344.0 [M+H]+; 1 H-NMR (600 MHz, CDCl 3 ): h 8.49 (s, 1H), 8.25 (brs, 1H), 8.17 (d, J = 2.28 Hz, 1H), 7.99 (d, J = 2.28 Hz, 1H), 7.86 (d, J = 8.91 Hz, 1H), 7.63 (dd, J = 1.59, 9.24 Hz, 1H), 6.86 (s , 1H), 4.10 (s, 3H), 3.07 (s, 3H). Example 22 2,4-difluoro-N-(5-(3-(3-hydroxyprop-1-yn-1-yl)-[1,2,4]triazolo-[4,3-a]pyridm-6- yl)-2-methoxypyridin-3-yl)benzenesulfonamide

Step 1) 5-bromo-2-hydrazinylpyridine

To a solution of 2,5-dibromopyridine (10.50 g, 44 mmoles) in 210 ml of pyridine was added hydrazine hydrate (80%, 8.85 g, 176.4 mmoles), and the mixture was heated to 110 oC and stirred for a further 2 hours, then cooled to room temperature and concentrated in vacuo. The residue was diluted with DCM (1500 ml). The resulting mixture was washed with aqueous NaOH solution (1M, 350 ml), dried over anhydrous Na 2 SO 4 , and concentrated in vacuo to give the title compound as a gray solid (7.87 g, 94.8%). MS (ESI, pos. ion) m/z: 188.0[M+H]+; 1 H-NMR (600 MHz, DMSO-d6): h 8.03 (d, J = 2.3 Hz, 1H), 7.67 (s, 1H), 7.59 (dd, J = 8.9, 2, 5Hz, 1H), 6.69 (d, J = 8.9Hz, 1H), 4.16 (s, 2H).

Step 2) 6-bromo-[1,2,4]triazolo[4,3-a]pyridine

[00244] To a mixture of 5-bromo-2-hydrazinylpyridine (7.87 g, 42 mmoles) in 200 ml of diethoxymethoxyethane was added p-toluenesulfonic acid (0.30 g, 1.7 mmol), and the mixture it was heated to 110°C and stirred for a further 20 hours, then cooled to room temperature, and concentrated in vacuo. The residue was diluted with H2O (150 ml). The resulting mixture was washed with aqueous NaHCO3 solution (saturated, 40 ml), and extracted with DCM (300 ml x 3). The combined organic phases were dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (PE/EtOAc (v/v) = 2/1) to give the title compound as a yellow solid (6.60 g, 79.77%). MS (ESI, pos. ion) m/z: 197.9 [M+H]+; 1 H-NMR (600 MHz, CDCl 3 ): h 8.82 (s, 1H), 8.34 (s, 1H), 7.75 (d, J = 9.7 Hz, 1H), 7.36 (d, J = 9.7 Hz, 1H).

Step 3) N-(5-([1,2,4]triazolo[4,3-a]pyridm-6-yl)-2-methoxypyridm-3-yl)-2,4-difluorobenzenesulfonamide

To a mixture of 6-bromo-[1,2,4]triazolo[4,3-a]pyridine (3.00 g, 15.2 mmol) in 65 ml of 1,4-dioxane was added Pd (dppf)Cl2^CH2Cl2 (1.24 g, 1.52 mmol) and a solution of sodium carbonate (4.00 g, 38 mmol) in 13 ml of water, and the mixture was degassed and charged with N2 for 3 times, then stirred at room temperature for a while, followed by the addition of 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2). -yl)pyridin-3-yl)benzenesulfonamide (7.78g, 18.2mmol), the mixture was degassed and charged with nitrogen 3 times, then heated to 90°C and stirred overnight. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v) = 30/1) to give the title compound as a gray solid (3.00 g, 47.33%). MS (ESI, pos. ion) m/z: 418.1 [M+H]+; 1 H-NMR (600 MHz, CDCl 3 ): h 10.36 (s, 1H), 9.26 (s, 1H), 8.91 (s, 1H), 8.39 (d, J = 2.3 Hz, 1H ), 7.97 (d, J = 2.3 Hz, 1H), 7.88 (d, J = 9.5 Hz, 1H), 7.76 (td, J = 8.5, 6.5 Hz , 1H), 7.70 (dd, J = 9.6, 1.7 Hz, 1H), 7.61-7.54 (m, 1H), 7.24-7.15 (m, 1H), 3.64 (s, 3H).

Step 4) N-(5-(3-bromo-[1,2,4]triazolo[4,3-a]pyridm-6-yl)-2-methoxypyridm-3-yl)-2,4-difluorobenzenesulfonamide

[00246] To a solution of N-(5-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide ( 6.60 g, 15.83 mmol) in CHCl 3 (130 ml) was added N-bromosuccinimide (2.96 g, 16.62 mmol) at -5 °C slowly and stirred for 3 hours. The reaction mixture was concentrated in vacuo and the residue was purified by a silica gel column chromatography (DCM/MeOH (v/v) = 50/1) to give the title compound as a white solid (2.80 g, 37.32%)). MS (ESI, pos. ion) m/z: 495.8 [M+H]+.

Step 5) 2,4-difluoro-N-(5-(3-(3-hydroxyprop-1-yn-1-yl)-[1,2,4]triazolo[4,3-a]pyridm-6- yl)-2-methoxypyridin-3-yl)benzenesulfonamide

[00247] To a mixture of N-(5-(3-bromo-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-methoxypyridin-3-yl)-2, 4-difluorobenzenesulfonamide (0.85 g, 1.79 mmol), Pd(PPh3)2Cl2 (0.126 g, 0.18 mmol) and CuI (34 mg, 0.18 mmol) in 8 ml of DMF was added triethylamine (0.904 g, 8.95 mmoles), and the mixture was degassed and charged with nitrogen 3 times, then prop-2-yn-1-ol (0.300 g, 5.37 mmoles) was added by syringe. The mixture was stirred at 50 °C under a N 2 atmosphere overnight, then cooled to room temperature, and concentrated in vacuo. The residue was diluted with water (25 ml). The resulting mixture was filtered and the filter cake was further purified by a silica gel column chromatography (DCM/MeOH (v/v) = 50/1) to give the title compound as a yellow solid (0.28 g, 33.21 %). MS (ESI, pos. ion) m/z: 471.8[M+H]+; 1 H-NMR (600 MHz, DMSO-d6): h 10.52 (s, 1H), 9.38 (s, 1H), 8.77 (s, 1H), 8.04-7.48 (m, 4H) , 7.24 (t, J = 7.6 Hz, 1H), 5.47 (d, J = 5.0 Hz, 1H), 4.58-4.39 (m, 1H), 3.67 ( s, 3H), 1.21 (d, J = 6.6 Hz, 3H). Example 23 2,4-difluoro-N-(5-(3-(3-hydroxybut-1-yn-1-yl)-[1,2,4]triazolo[4,3-a]pyridm-6-yl )-2-methoxypyridm-3-yl)benzenesulfonamide

[00248] To a mixture of N-(5-(3-bromo-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-methoxypyridin-3-yl)-2, 4-difluorobenzenesulfonamide (0.85 g, 1.79 mmol), Pd(PPh3)2Cl2 (0.126 g, 0.18 mmol) and CuI (34 mg, 0.18 mmol) in 8 ml of DMF was added triethylamine (0.904 g, 8.95 mmoles), and the mixture was degassed and charged with nitrogen 3 times, then but-3-yn-2-ol (0.376 g, 5.37 mmoles) was added by syringe. The mixture was stirred at 50 °C under a N 2 atmosphere overnight, then cooled to room temperature, and concentrated in vacuo. The residue was diluted with water (25 ml). The resulting mixture was filtered and the filter cake was further purified by a silica gel column chromatography (DCM/MeOH (v/v) = 50/1) to give the title compound as a yellow solid (0.28 g, 32.25%). MS (ESI, pos. ion) m/z: 485.9[M+H]+; 1 H-NMR (600 MHz, DMSO-d6): h 10.52 (s, 1H), 9.38 (s, 1H), 8.77 (s, 1H), 8.04-7.48 (m, 4H) , 7.24 (t, J = 7.6 Hz, 1H), 5.47 (d, J = 5.0 Hz, 1H), 4.58-4.39 (m, 1H), 3.67 ( s, 3H), 1.21 (d, J = 6.6 Hz, 3H). Example 24 N-(5-(3-cyanoimidazo[1,2-b]pyridazin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[00249] 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (1 .47 g, 3.45 mmoles), 6-bromoimidazo[1,2-b]pyridazine-3-carbonitrile (513 mg, 2.3 mmoles), Pd(dppf)Cl2^CH2Cl2 (188 mg, 0.23 mmoles) ) and NebCX); (975 mg, 9.2 mmoles) were placed in a two-neck flask, and the mixture was degassed and charged with N2 3 times, followed by the addition of 1,4-dioxane (50 ml) and water (10 ml) . The resulting mixture was degassed and charged with N2 3 times, then heated to 90°C and stirred for a further 5 hours. The mixture was then cooled to room temperature, and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) =2/3) to give the title compound as a pale yellow solid (580 mg, 57 %). MS (ESI, pos. ion) m/z: 443.2 [M+H]+; Purity: 97.1%; 1 H-NMR (400 MHz, DMSO-d6): h 10.53 (s, 1H), 8.77 (d, J = 2.3 Hz, 1H), 8.60 (s, 1H), 8.46 (d , J = 9.6 Hz, 1H), 8.29 (d, J = 2.3 Hz, 1H), 8.17 (d, J = 9.7 Hz, 1H), 7.86-7.81 (m, 1H), 7.61-7.53 (m, 1H), 7.24 (td, J = 8.4, 2.0 Hz, 1H), 3.76 (s, 3H).

BIOLOGICAL TEST

The efficacy of the compounds disclosed herein as inhibitors of PI3 kinases and mTOR kinases can be evaluated as follows. Test results demonstrate that certain compounds disclosed herein potentially inhibit PI3Ks and mTOR.

[00251] The LC/MS/MS system used in the analysis consists of an Agilent Series 1200 vacuum degasser, binary pump, reservoir-plate autosampler, thermostatically controlled column compartment, the Agilent G6430 Triple Quadripolar Mass Spectrometer with an electrospray ionization (ESI) source. Quantitative analysis was performed using the MRM mode. The parameters for the MRM transitions are in Table A. Table A

[00252] An Agilent XDB-C18 column, 2.1 x 30 mm, 3.5 oM was used for the analysis. 5 µl of the samples were injected. Analysis condition: The mobile phase was 0.1% formic acid in water (A) and 0.1% formic acid in methanol (B). The flow rate was 0.4 ml/min. and the Mobile Phase gradient was as in Table B. Table B

[00253] Alternatively, an Agilent Series 6330 LC/MS/MS spectrometer equipped with G1312A binary pumps, a G1367A autosampler and a G1314C UV detector were used in the analysis. An ESI source was used in the LC/MS/MS spectrometer. Analysis was done in positive ion mode as appropriate and the MRM transition for each analyte was optimized using standard solution. A Capcell MP-C18 100 x 4.6 mm I.D., 5 µM column (Phenomenex, Torrance, California, USA) was used during the analysis. The mobile phase was 5 mM ammonium acetate, 0.1% MeOH in water (A): 5 mM ammonium acetate, 0.1% MeOH in acetonitrile (B) (70/30, v/v) . The flow rate was 0.6 ml/min. The column was kept at room temperature. 20 µL of the samples were injected.

Example A: Compound Stability in Human and Rat Liver Microsomes

Human and rat liver microsome incubations were conducted in duplicate in polypropylene tubes. Typical incubation mixtures consisted of human and rat liver microsomes (0.5 mg protein/ml), compounds of interest (5 µM) and NADPH (1.0 mM) in a total volume of 200 µn of buffer. potassium phosphate (PBS, 100 mM, pH = 7.4). Compounds were dissolved in DMSO and diluted with PBS such that the final concentration of DMSO was 0.05%. The enzymatic reactions were started with the addition of protein after a pre-incubation and incubated in an open air water bath at 37 oC. Reactions were terminated at various time points (0, 5, 10, 15, 30, 60 min) by the addition of an equal volume of ice-cold acetonitrile. Samples were stored at -80 oC until LC/MS/MS assays.

The concentrations of compounds in the human and rat liver microsome incubation mixtures were determined by an LC/MS/MS method. The linearity ranges in the concentration range were determined for each of the tested compounds.

[00256] A parallel incubation was performed using denatured microsomes as the negative control, and reactions were terminated at various time points (0, 15, 60 min) after incubation at 37 oC.

[00257] Dextromethorphan (70 μO+ was selected as the positive control, and reactions were terminated at various time points (0, 5, 10, 15, 30, 60 min) after incubation at 37 oC. Both control samples positive and negative were included in each assay to ensure the integrity of the microsomal incubation system.

Data analysis

[00258] Compound concentrations in human or rat liver microsome incubations were plotted as a percentage of the relevant zero time point control for each reaction. In vivo CLint were extrapolated (ref.: Naritomi Y, Terashita S, Kimura S, Suzuki A, Kagayama A, Sugiyama Y. Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans Drug Metabolism and Disposition 2001, 29: 13161324). Table 2 Stability of human and rat liver microsomes

Example B: Evaluation of Pharmacokinetics After Intravenous and Oral Administration of the Compounds Disclosed Here in Mice, Rats, Dogs and Monkeys

Tabela 4 Perfis farmacocinéticos em Camundongos, Cães e Macacos[00259] The compounds disclosed herein are evaluated in pharmacokinetic studies in mice, rats, dogs or monkeys. Compounds are administered as an aqueous solution, 2% HPMC + 1% TWEEN®80 in aqueous solution, 5% DMSO + 5% solutol in saline, 4% MC suspension or capsule. For intravenous administration, animals are generally given a dose of 1 or 2 mg/kg. For oral (po) dosing, mice and rats are usually given a dose of 5 or 10 mg/kg, and dogs and monkeys are usually given a dose of 10 mg/kg. Blood samples (0.3 ml) are taken at time points of 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12 and 24 h or time points of 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h and centrifuged at 3,000 or 4000 rpm for 2 to 10 min. Plasma solutions are collected, stored at -20 oC or -70 oC until analyzed by LC/MS/MS as described above Table 3 Pharmacokinetic profiles in rats

Table 4 Pharmacokinetic Profiles in Mice, Dogs and Monkeys

Example C: Kinase Activity Assay

The efficacy of the compounds disclosed herein as inhibitors of PI3 kinases and mTOR kinases can be evaluated as follows. General Description for Kinase Assays

[00261] Kinase assays can be performed by measuring the incorporation of y-33P ATP into immobilized myelin basic protein (MBP). High-binding white 384 well plates (Greiner) are coated with MBP (Sigma #M-1891) by incubating 60 µl/20 µg/ml MBP reservoir in Tris-buffered saline (TBS; 50 mM Tris pH). 8.0, 138 mM NaCl, 2.7 mM KCl) for 24 h at 4 oC. Plates are washed 3x with 100 µl of TBS. Kinase reactions are performed in a total volume of 34 µl in kinase buffer (5 mM Hepes pH 7.6, 15 mM NaCl, 0.01% bovine gamma globulin (Sigma #I-5506), 10 mM MgCl 2 , 1 mM DTT, 0.02% TritonX-100). Compound dilutions are made in DMSO and added to assay wells at a final DMSO concentration of 1%. Each data point is measured in duplicate, and at least two duplicate assays are performed for each individual compound determination. Enzyme is added at final concentrations of 10 nM or 20 nM, for example. A mixture of unlabeled ATP and y-33P ATP is added to initiate the reaction (2 x 106 cpm of y-33P ATP per well (3000 Ci/mmol) and typically 10 µM of unlabeled ATP. Reactions are performed by 1 h at room temperature with shaking. Plates are washed 7x with TBS, followed by the addition of 50 µl/scintillation fluid reservoir (Wallac) Plates are read using a Wallac Trilux counter. ; several other formats are possible, as known to a person of skill in the art.

[00262] The above test procedure can be used to determine the IC50 for inhibition and/or the inhibition constant, Ki. The IC50 is defined as the concentration of compound required to reduce enzyme activity by 50% under the test condition. The IC50 value is estimated by preparing a 10-point curve using a ^ log dilution series (for example, a typical curve can be prepared using the following compound concentrations: 10 μM, 3 μM, 1 μM, 0, 3 μM, 0.1 μM, 0.03 μM, 0.01 μM, 0.003 μM, 0.001 μM and 0 μM).

PI3 KIANSE GENERAL TEST PROTOCOL PI3K (r332g1r:7g) (h) [Non-radioactive assay]

[00263] PI3K (p110g/p85g) (h) is incubated in assay buffer containing 10 µM phosphatidylinositol 4,5-bisphosphate and MgATP (concentration as required). The reaction is started by adding the ATP solution. After incubation for 30 minutes at room temperature, the reaction is stopped by the addition of a stop solution containing EDTA and biotinylated phosphatidylinositol-3,4,5-trisphosphate. Finally, detection buffer is added, which contains anti-GST monoclonal antibody labeled with europium, GRP1 PH domain labeled with GST, and allophycocyanin streptavidin. The plate is then read in the time-resolved fluorescence mode and the time-resolved fluorescence signal (HTRF) is determined according to the formula HTRF = 10000 x (Em665nm/Em620nm).

PI3K (r332β1r:7g) (h) [Non-radioactive assay]

PI3K *r332β1r:7g) (h) is incubated in assay buffer containing 10 µM phosphatidylmositol-4,5-bisphosphate and MgATP (concentration as required). The reaction is started by adding the MgATP mixture. After incubation for 30 minutes at room temperature, the reaction is stopped by the addition of EDTA containing stopping solution and biotinylated phosphatidylinositol-3,4,5-trisphosphate. Finally, detection buffer is added, which contains anti-GST monoclonal antibody labeled with europium, GRP1 PH domain labeled with GST, and streptavidin-allophycocyanin. The plate is then read in the time-resolved fluorescence mode and the homogeneous time-resolved fluorescence (HTRF) signal is determined according to the formula HTRF = 10000 x (Em665nm/Em620nm).

PI3K (p110f1r:7g+ (h) [Non-radioactive assay]

[00265] PI3K (p110f/p85g) (h) is incubated in assay buffer containing 10 µM phosphatidylinositol-4,5-bisphosphate and MgATP (concentration as required). The reaction is started by adding the MgATP mixture. After incubation for 30 minutes at room temperature, the reaction is stopped by the addition of EDTA containing stopping solution and biotinylated phosphatidylinositol-3,4,5-trisphosphate. Finally, detection buffer is added, which contains anti-GST monoclonal antibody labeled with europium, GRP1 PH domain labeled with GST, and streptavidin-allophycocyanin. The plate is then read in the time-resolved fluorescence mode and the homogeneous time-resolved fluorescence (HTRF) signal is determined according to the formula HTRF = 10000 x (Em665nm/Em620nm).

PI3K (p120y+ (h) [Non-radioactive assay]

[00266] PI3K (p120y + (h) is incubated in assay buffer containing 10 μM phosphatidylinositol-4,5-bisphosphate and MgATP (concentration as required) The reaction is started by adding the MgATP mixture. After incubation by 30 minutes at room temperature, the reaction is stopped by the addition of EDTA containing stop solution and biotinylated phosphatidylinositol-3,4,5-trisphosphate. Finally, detection buffer is added, which contains anti-GST monoclonal antibody labeled with europium, GRP1 PH domain labeled with GST and streptavidin-allophycocyanin. The plate is then read in the time-resolved fluorescence mode and the homogeneous time-resolved fluorescence (HTRF) signal is determined according to the formula HTRF = 10000 x (Em665nm /Em620nm).

mTOR (h)

[00267] mTOR (h) is incubated with 50 mM HEPES pH 7.5, 1 mM EDTA, 0.01% Tween 20, 2 mg/ml substrate, 3 mM Manganese Chloride and ]-33P -ATP] (specific activity approx. 500 cpm/pmol, concentration as required). The reaction is started by adding the MnATP mixture. After incubation for 40 minutes at room temperature, the reaction is stopped by adding a 3% phosphoric acid solution. 10 μn of the reaction is then spotted on a P30 filter mat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol before drying and scintillation counting.

The kinase assays described herein were performed at Millipore UK Ltd, Dundee Technology Park, Dundee DD2 1SW, UK.

[00269] The compounds disclosed herein exhibited potent activities in the PI3Kg*j+ and mTOR(h) assays. Table 5 listed the IC50s of some examples described herein in the PI3Kg(h) and mTOR(h) assays. Table 5 Kinase Inhibition Data

[00270] Alternatively, the kinase activities of compounds can be measured using KINOMEscan®, which is based on a competition binding assay that quantitatively measures the ability of a compound to compete with an immobilized ligand, targeting the active site. The assay was performed by combining three compounds: DNA-labeled kinase; immobilized ligand; and a test compound. The ability of the test compound to compete with the immobilized ligand was measured by quantitative DNA tag PCR.

[00271] For most assays, kinase-labeled T7 phage strains were prepared in an E. coli host derived from strain BL21. E. coli was grown to log phase and infected with T7 phage and incubated with shaking at 32°C until lysis. Lysates were centrifuged and filtered to remove cell debris. The remaining kinases were produced in HEK-293 cells and subsequently labeled with DNA for qPCR detection. Streptavidin coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for the kinase assays. Ligand beads were blocked with excess biotin and washed with blocking buffer (SEABLOCK® (Pierce), 1% BSA, 0.05% TWEEN®20, 1 mM DTT) to remove unbound ligand and to reduce the non-specific binding. Binding reactions were set up by combining kinases, ligand affinity beads, and test compounds in 1x binding buffer (20% SEABLOCK®, 0.17x PBS, 0.05% TWEEN®20, 6mM DTT). All reactions were performed in 96-well polystyrene well plates in a final volume of 0.135 ml. Assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (1x PBS, 0.05% TWEEN®20). The beads were then resuspended in elution buffer (1x PBS, 0.05% TWEEN®20, 0.5 µM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluates was measured by qPCR.

The kinase assays described herein were performed using KINOMEscan® Profiling Service at DiscoveRx Corporation, 42501 Albrae St. Fremont, CA 94538, USA.

Example D: Tumor Xenograft Models

[00273] The efficacy of the compounds disclosed herein was evaluated in a standard murine model of tumorigenesis. Human tumor cells (ATCC U87MG glioblastoma cells) were culture-expanded, harvested, and injected subcutaneously into the hind flank of 6- to 7-week-old female athymic nude mice (BALB/cA nu/nu, Hunan SLAC Laboratory Animal , Co.) (n = 6 to 10 for the vehicle group and for each dosage group). When tumors reached a volume of 100 to 250 mm3, animals were randomly assigned to vehicle control (eg 5% DMSO + 70% Captisol® (30%), 7% HCl (pH1), 18% Captisol® (30%); or 7% DMSO, 7% HCl (pH 1), 70% Captisol® (30%), 16% Captisol® (30%), or the like) and groups of compound. Subsequent compound administration by oral gavage begins anywhere from day 0 to day 15 after tumor cell inoculation and generally continues with once daily for the duration of the experiment.

Tumor Growth Inhibition Analysis (TGI)

[00274] Tumor growth progression is assessed by tumor volumes and recorded as a function of time. The long (L) and short (W) axes of subcutaneous tumors were measured with calipers twice weekly, and tumor volume (TV) calculated as (L x W2)/2). The TGI was calculated from the difference between the mean tumor volumes of vehicle-treated and drug-treated mice, expressed as a percentage of the mean tumor volume of the vehicle-treated control group, by the following relationship:

[00275] The initial statistical analysis is done by repeated measures analysis of variation (RMANOVA), followed by Scheffe's post hoc test for multiple comparisons. Vehicle alone (5% DMSO + 70% Captisol® (30%), 7% HCl (pH 1), 18% Captisol® (30%); or 7% DMSO, 7% HCl (pH 1 ), 70% Captisol® (30%), 16% Captisol® (30%), or the like) is the negative control. Table 6 Selected results from tumor xenograft model studies (U87MG)

[00276] Finally, it should be mentioned that there are alternative ways to implement the present invention. Accordingly, the present embodiments are to be considered as illustrative and not restrictive and the invention is not to be limited to the details given herein, but may be modified within the scope and equivalents of the appended claims. All publications and patents cited herein are incorporated by reference.

Claims (8)

1. Compound, characterized by the fact that it has the Formula 1

or a pharmaceutical salt thereof, wherein: each of W1, W2 and W3 is independently N or CRc; Z is CN; Y is alkyl (C1-C6), cycloalkyl (C3-C6), heterocyclyl (C3-C6), -alkylene (C1-C4)-cycloalkyl (C3-C6), -alkylene (C1-C4)-heterocyclyl (C3C6) , alkenyl (C2-C6), alkynyl (C2-C6), aryl (C6-C10), or 5- to 10-membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, each one from alkyl (C1-C6), cycloalkyl (C3-C6), heterocyclyl (C3-C6), -alkylene (C1-C4)-cycloalkyl (C3-C6), - alkylene (C1-C4)-heterocyclyl (C3-C6 ), alkenyl (C2-C6), alkynyl (C2-C6), aryl (C6-C10) and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, CN, N3, ORa, Sra, NRaRb, -C(=O)NRaRb, alkyl (C1-C6), haloalkyl (C1C6), alkenyl (C2-C6), alkynyl (C2-C6), -alkylene (C1 -C4)-CN, -(C1-C4)alkylene-ORa, -(C1-C4)alkylene-NRaRb, (C6-C10) aryl, and 5- to 10-membered heteroaryl; each Ra and Rb is independently H or (C1-C6) alkyl, wherein each of the (C1-C6) alkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, CN, N3 , OH, NH 2 , alkoxy (C 1 -C 6 ), and alkyl (C 1 -C 6 )amino; R1 is ORa, where Ra is (C1-C6) alkyl; and each Rc is independently H. 2. Compound according to claim 1, characterized in that each of W1 and W2 is independently N or CRc, W3 is CRc. 3. Compound according to claim 1, characterized in that R1 is OCH3 or OCH2CH3. 4. Compound according to claim 1, characterized in that it has one of the following structures:

5. Pharmaceutical composition, characterized in that it comprises the compound as defined in any one of claims 1 to 4 and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof. 6. Pharmaceutical composition according to claim 5, characterized in that it further comprises an additional therapeutic agent comprising a chemotherapeutic agent, an antiproliferative agent, an agent to treat atherosclerosis, an agent to treat pulmonary fibrosis or a combination thereof. 7. Pharmaceutical composition according to claim 6, characterized in that the additional therapeutic agent is chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate , fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirrubicin, mitotambicin, daunoxantomycin, mitotambicin, mitotambicin, mitotambicin, mitotambicin of gonadorelin, megestrol, prednidone, dexamethasone, methylprednisolone, thalidomide, interferon alpha, leucovorin, sirolimus, tensirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, dabbranizomib, dabbrutinib, brisutinib, dabfennib, bris, brisinib, dacomitinib, danusertib, dasatinib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, nilotinib, niraparib, lenvatinib, oprozomib, oprozomib, motetinib, rucaparib, ruxolitinib, saracatinib, saridegib, sorafenib, sunitinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, tivantinib, alemtuzuma , nimotuzumab, ofatumumab, panitumumab, ramucirumab, rituximab, tositumomab, trastuzumab, or a combination thereof. 8. Use of a compound as defined in any one of claims 1 to 4 or a pharmaceutical composition as defined in any one of claims 5 to 7, characterized in that it is for the manufacture of a medicine to prevent, control , treat or lessen the severity of a proliferative disorder in a patient, where the proliferative disorder is metastatic cancer, colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, skin cancer, thyroid cancer, head and neck cancer, prostate cancer, pancreatic cancer, CNS cancer, glioblastoma, a myeloproliferative disorder, atherosclerosis or pulmonary fibrosis.